Drug eluting stent and method of use of the same for enabling restoration of functional endothelial cell layers

ABSTRACT

The present disclosure relates to drug eluting stents, methods of making, using, and verifying long-term stability of the drug eluting stents, and methods for predicting long term stent efficacy and patient safety after implantation of a drug eluting stent. In one embodiment, a drug eluting stent may include a stent framework; a drug-containing layer; a drug embedded in the drug-containing layer; and a biocompatible base layer disposed over the stent framework and supporting the drug-containing layer. The drug-containing layer may have an uneven coating thickness. In addition or in alternative, the drug-containing layer may be configured to significantly dissolve/dissipate/disappear between 45 days and 60 days after stent implantation. Stents of the present disclosure may reduce, minimize, or eliminate patient risks associated with the implantation of a stent, including, for example, restenosis, thrombosis, and/or MACE.

CROSS-REFERENCE TO RELATED APPLICATIONS CROSS REFERENCE TO RELATEDAPPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 15/797,862, filed Oct. 30, 2017; which is a continuation-in-part ofU.S. patent application Ser. No. 13/850,679, filed Mar. 26, 2013, nowpatented as Pat. No. 9884142, issued Feb. 6, 2018; which is acontinuation of U.S. patent application Ser. No. 11/808,926, filed Jun.13, 2007, now abandoned; which claims benefit of priority to U.S.Provisional Patent Application No. 60/812,990, filed Jun. 13, 2006, theentire contents of which are all incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to drug eluting stents, methods of makingand using the ding eluting stents, as well as methods for predictinglong term stent efficacy and patient safety after implantation of a drugeluting stent. More specifically, and without limitation, the presentdisclosure relates to the design of a drug eluting stent comprising astent framework (e.g., metal based or made with biodegradable materials)and a layer or layers covering all or part of the surface of said stent,capable of hosting a drug and releasing it in a sustained manner, insuch a way that patient risks associated with the implantation of saiddrug eluting stent are minimized or eliminated. The stents disclosedherein are capable of enabling functional restoration of endothelialcell layers after implantation.

BACKGROUND

Over the years, the use of coatings for medical devices and drugdelivery has become a necessity, notably for augmenting the capabilitiesof medical devices and implants. Drug eluting medical devices haveemerged as a leading biomedical device for the treatment ofcardiovascular disease.

Heart disease and heart failure are two of the most prevalent healthconditions in the U.S. and the world. In coronary artery disease, theblood vessels in the heart become narrow. When this happens, the oxygensupply is reduced to the heart muscle. A primary treatment of coronaryartery disease was initially done by surgery, e.g., CABG (CoronaryArtery Bypass Graft), which are normal and efficient proceduresperformed by cardiac surgeons. The mortality and morbidity, however,were rather high.

In the 1960s, some physicians developed a less invasive treatment byusing medical devices. These devices were inserted through a smallincision at the femoral artery. For example, balloon angioplasty (whichmay be used to widen an artery that has become narrowed using a ballooncatheter which is inflated to open the artery and is also termed PTCA(Percutaneous Transluminal Coronary Angioplasty)) is used in patientswith coronary artery disease. Following balloon angioplasty,approximately 40 to 50% of coronaries arteries are generally affected byrestenosis (the re-narrowing of a blood vessel after it has been opened,usually by balloon angioplasty), usually within 3 to 6 months due toeither thrombosis (the development of a blood clot in the vessels whichmay clog a blood vessel and stop the flow of blood) or abnormal tissuegrowth. As a result, restenosis constitutes one of the major limitationsto the effectiveness of PTCA.

The introduction of the bare metal stent (BMS) in the late 1980s, whenused to keep coronary arteries expanded, partially alleviated thisproblem, as well as that of the dissections of arteries upon ballooninflation in the PTCA procedure.

The stent is a mesh tube mounted on a balloon catheter (e.g., a longthin flexible tube that can be inserted into the body). In this example,the stent is threaded to the heart. However, the BMS initially continuedto be associated with a general restenosis rate of around 25% ofpatients affected 6 months after stent insertion. Usually, stent strutsend up embedded by the arterial tissue in growth. This tissue istypically made of smooth muscle cells (SMCs), the proliferation of whichmay be provoked by the initial damaging of the artery upon stentapposition.

As depicted in FIG. 1 , the whole inner surface of the vessel 100 iscovered by “active” of functional ECs 101, i.e. endothelial cellsspontaneously producing nitrogen oxide (NO), a small molecule acting asa signal to stop the proliferation of SMCs 103 underneath. This naturalrelease of NO by ECs 101 takes place generally when ECs 101 are inimmediate contact to one another, e.g., paving the inner surface of theartery by a continuous and closely packed film.

When a stent (or a balloon) is inflated inside vessel 150, stent stmtsin contact with the vessel walls will partly destroy the EC layer andinjure the artery, e.g. at contact points 105 a and 105 b. The naturalrelease of NO is thus - at least locally at contact points 105 a and 105b - highly perturbed. This injury may trigger the proliferation of SMCsas a repair mechanism, e.g., SMCs 107 a and 107 b. The uncontrolledproliferation of SMCs may cause the re-closing of the vessel, or“re-stenosis.” If, while SMCs 107 a and 107 b are proliferating, ECs 101can also proliferate and eventually cover again the stent stmts and SMCs107 a and 107 b via a continuous film, then the NO release may berestored and the proliferation of SMC's may be stopped. Consequently,the risk of restenosis may be lessened (if not eliminated) and thesituation may stabilize.

One of the biggest challenges of the interventional cardiology industrysince the 1990s has been to first understand and then secure this “race”for complete EC coverage and restoring the EC layer functions. Theendothelium is a monolayer of cells lining the inside of all blood andlymph vasculature. One important function of the endothelium is toregulate the movement of fluid, macromolecules, and white blood cellsbetween the vasculature and the interstitial tissue. This is mediated,in part, by the ability of endothelial cells to form strong cell cellcontacts by using a number of transmembrane junctional proteins,including VE-Cadherin and p120-catenin. Colocalization of the twoproteins is an indication of a well-functioning endothelial cell layer.

Two strategies have been historically considered to restore an arteryfollowing stent implantation. One goal of most Drug Eluting Stents (DES)designs is to promote the proliferation of active endothelial cells(ECs) to accelerate their migration and eventual coverage of the surfaceof the stent. If these new ECs are active, e.g., form a continuous andclose packed film, they usually spontaneously release NO and therebyhinder the proliferation of SMCs.

Another goal of most DES designs is to inhibit the proliferation ofsmooth muscle cells (SMCs). Generally, this has been targeted via thelocal release of an anti-proliferative agent (usually ananti-angiogenesis drug, similar to anti-cancer agents) from the surfaceof the stent.

Many DES on the market are made on the basis of a polymeric releasematrix from which the drug is eluted. First and second generation stentswere often coated with a biostable polymer. In such stents, the polymerstays permanently on the stent, and is generally assumed to have littleeffect both on the inflammatory response and the proliferation of ECs.In sole cases, however, these stents do not release 100% of the drugthat their coating is hosting. In particular, sometimes the majority ofthe drug remains in the polymer coating for long periods of time.Furthermore, most drugs used so far are not selective and tend toinhibit the proliferation of ECs more than that of SMCs.

This drawback may have dramatic and potentially lethal consequences forthe patients and, thus, for the DES industry. Indeed, despite thepossible reduction in restenosis from ca. 20% with Bare Metal Stents(BMS) to ca. 5% with Drug Eluting Stents (DES) in the first year, themassive introduction of DES brought two new challenges: (1) thephenomenon of late thrombosis, i.e., re-clotting of the artery one yearor more after stent implantation, and (2) progressive growth of theneo-intimal layer leading to restenosis again. Accordingly, what DES hasgenerally accomplished is to delay the occurrence of restenosis yetcause other complications, such as thrombosis, in the years after theDES implantation.

The implantation of bare metal stents is understood to be a source ofthrombosis, in addition to restenosis, but the former is generallyhandled by a systemic Dual Anti-Platelet Therapy (DAPT) associating twoanti-thrombotic agents, e.g., aspirin and clopidogrel. For example,patients in whom a stent was implanted were often prescribed such DAPTfor 1 to 2 months. With drug eluting stents, numerous cases ofre-clotting of the artery due to coagulation (thrombosis) afterinterruption of the DAPT have been reported. Accordingly, manycardiologists maintain the DAPT for 3, 6, 9 and now 12 months or more.By 2005-2006, several cases were reported that myocardial infarctionwith total stent thrombosis may occur only a couple of weeks afterinterruption of an 18-month DAPT.

Late thrombosis is an abrupt complication which can be lethal whenoccurring if the patient is not under medical follow-up or—even if thepatient is—while the patient is away from the cathlab or from anadequately equipped medical centre. Moreover, DAPT may present abottleneck that is difficult to manage, as some patients may decide bythemselves to stop it after a period of use, or forget to have theirmedicines refilled or to take their medicines, or may have to undergo aclinical intervention which could not be anticipated, and are thus inthe position to have to stop the anti-thrombotic treatment.

The exact causes of late thrombosis still are not fully understood.Pathologists estimate that late thrombosis reveals an incompletecoverage of the stent by ECS, leaving metallic or polymeric materials incontact with the blood over prolonged periods, on which plateletadhesion is likely to occur, which may lead to catastrophicprecipitation of a thrombus. Alternative interpretations propose thatthe incomplete coverage by ECs may be the result of the incompleterelease of the drug from the release layer, which may inhibit theproliferation of ECs in their attempt to migrate and cover the surfaceof said polymer+drug+SMC layer.

The thickness of the stent struts may further present a source ofhindrance of the proliferation of ECs. Whenever ECs have to proliferateon a surface, the rate of their proliferation is often negatively (andlargely) influenced by the height of obstacles that they have toovercome on this surface towards complete coverage. Accordingly, not allstent designs and drug release profiles are equal. For example, when theDES is apposed in the artery, the injured EC layer has to overcomeobstacles with a height roughly equal to the thickness of the stentstrut+the thickness of the drug release polymer layer+the thickness ofthe SMC layer which has started to form. The former two thicknesses arerelated to the design of the DES, while the latter thickness is linkedto the efficacy of the drug, its loading in the release layer, and itsrelease rate. Thus a need still exists for developing a new stent andmethod of making a stent that can decrease patient risks associated withthe implantation of stents restenosis, thrombosis, MACE).

SUMMARY

The present disclosure relates to drug eluting stents, as well asmethods of making and using the drug eluting stents, and a method ofpredicting stent efficacy and patient safety. In one embodiment, thedrug eluting stent (1) combines four parts: a stent framework (2), adrug-containing layer (3), a drug (4), and a biocompatible base layersupporting the drug-containing layer (5). In one embodiment, the stentand the method of making the stent are designed so as to manipulate thetime to achieve a sufficient re-endothelialization of the stentsurface/vascular wall and improve endothelium function restoration bymanipulating the thickness of the drug-containing layer and thedistribution of that thickness. In one embodiment, the thickness of thedrug-containing layer in the luminal side is different from thethickness in the abluminal side. In one embodiment, the stent minimizeslate thrombosis, i.e. re-clotting of the artery one year or more afterstent implantation and progressive thickness of the neo-intimal layerleading to restenosis again. In one embodiment, the stent and the methodof making the stent are such that they reduce the number or frequency ofmajor adverse cardiac events (MACE). In one embodiment, neointimalcoverage or re-endothelialization of the surface of stent struts within90 days significantly improves strength efficacy and patient safety.

A stent framework (2) may be fabricated from a single (or more) piecesof metal or wire or tubing. For example, the stent framework maycomprise cobalt-chromium (e.g., MP35N or MP20N alloys), stainless steel(e.g., 316L), nitinol, tantalum, platinum, titanium, suitablebiocompatible alloys, other suitable biocompatible materials, and/orcombinations thereof.

In some embodiments, the stent framework (2) may be biodegradable. Forexample, the sent framework (2) may be fabricated from magnesium alloy,polylactic acid, polycarbonate poylmers, salicylic acid polymers, and/orcombinations thereof. In other words, any biocompatible but alsobiodegradable materials which can be fabricated in such way that theradical force is sufficient strong to be implantable and support tostabilize the lesion and vessel retraction, but where the thickness ofthe stent is less than 120 um.

In other embodiments, the stent framework (2) may be fabricated from oneor more plastics, for example, polyurethane, teflon, polyethylene, orthe like.

A drug-containing layer (3) may be made from polymers and may comprise alayer or layers covering all or part of the stent surface. Furthermore,a drug-containing layer (3) may be capable of hosting a drug (4) andreleasing the drug (4) in a sustained manner.

In one embodiment, the drug-containing layer may have an uneven coatingthickness. For example, a thickness of the drug-containing layer on aluminal side of the stent and a thickness of the drug-containing layeron a lateral side of the stent is less than a thickness of thedrug-containing layer on an abluminal side of the stent.

In one embodiment, for example on account of the uneven coatingthickness, the drug-containing layer may release the drug within 30 daysof implantation within a vessel. The release time may be verified, forexample, using a standard animal PK study. Accordingly, when the drugeluting stent (1) is implanted into the human body vessel, the drug (4)may be released from coating (3) within 30 days or less. In otherembodiments, the drug is released at different rates, such as 45 days orless, 60 days or less, 90 days or less, 120 days or less.

In some embodiments, the drug may be included only on an abluminal sideof the stent.

In embodiments where the drug-containing layer (3) is made from abio-degradable or bio-absorbable polymer/s, the polymer(s) may bebio-degraded or bio-absorbed between 45 days and 60 days of implantationof the stent. In other embodiments, the polymer/polymers is/arebio-degraded or bio-absorbed within, such as 45 days or less, 60 days orless, 90 days or less, 120 days or less.

In some embodiments, the polymer on a luminal side and/or a lateral sideof the stent may differ from the polymer on an abluminal side. Forexample, one or more polymers forming the drug-containing layer on aluminal side of the stent and the drug-containing layer on a lateralside of the stent degrade faster than one or more polymers forming thedrug-containing layers on an abluminal side of the stent.

The biocompatible base layer (5) may be formed over the stent framework(2) and may have a more biocompatible surface than the stent framework(2). For example, the biocompatible base layer (5) may be made from polyn-butylmethacrylate, PTFE, PVDF-HFP,poly(styrene-b-isobutylene-b-styrene), Parylene C, PVP, PEVA, SBS, PC,TiO2 or any material that has good biocompatibility (or combinationsthereof).

Additional exemplary embodiments of this disclosure are provided belowand numbered for reference purposes only:

-   -   1. A drug eluting stent, comprising:        -   a stent framework;        -   a drug-containing layer;        -   a drug embedded in the drug-containing layer; and        -   a biocompatible base layer disposed over the stent framework            and supporting the drug-containing layer,        -   wherein the drug-containing layer has an uneven coating            thickness, optionally,        -   wherein the drug-containing layer is configured to            completely dissolve/between 45 days and 60 days after            implantation of the drug eluting stent.    -   2. The drug eluting stent of embodiment 1, wherein the        drug-containing layer is configured to release the drug within        30 days of implantation within a vessel.    -   3. The drug eluting stent of embodiment 1, wherein a thickness        of the drug-containing layer on a luminal side of the stent and        a thickness of the drug-containing layer on a lateral side of        the stent is less than a thickness of the drug-containing layer        on an abluminal side of the stent.    -   4. The drug eluting stent of embodiment 3, where a ratio between        the thickness of the drug containing layer on the luminal side        and the thickness of the drug-containing layer on the abluminal        side is between 2:3 and 1:7.    -   5. The drug eluting stent of embodiment 3 or 4, where a ratio        between the thickness of the drug-containing layer on the        lateral side and the thickness of the drug-containing layer on        the abluminal side is between 2:3 and 1:7.    -   6. The drug eluting stent of any one of embodiments 1 through 5,        wherein the drug is embedded only on the drug-containing layer        on an abluminal side of the stent.    -   7 The drug eluting stent of any one of embodiments 1 through 6,        wherein the stent framework is fabricated from a single piece of        metal, wire, or tubing.    -   8. The drug eluting stent of embodiment 7, wherein the metal        comprises at least one of stainless steel, nitinol, tantalum,        cobalt-chromium MP35N MP20N alloys, platinum, and titanium.    -   9. The drug eluting stent of any one of embodiments 1 through 6,        wherein the stent framework is fabricated from a biodegradable        material.    -   10. The drug eluting stent of any one of embodiments 1 through        9, wherein the drug comprises at least one of an        antithrombogenic agent, an anticoagulant, an antiplatelet agent,        an antineoplastic agent, an antiproliferative agent, an        antibiotic, an anti-inflammatory agent, a gene therapy agent, a        recombinant DNA product, a recombinant RNA product, a collagen,        a collagen derivative, a protein analog, a saccharide, a        saccharide derivative, an inhibitor of smooth muscle cell        proliferation, a promoter of endothelial cell migration,        proliferation, and/or survival, and combinations of the same.    -   11. The drug eluting stent of embodiment 10, wherein the drug        comprises sirolimus and/or a derivative or analog.    -   12. The drug eluting stent of embodiment 1, wherein the        drug-containing layer has a thickness between 5 and 12 μm.    -   13. The drug eluting stent of embodiment 1, wherein the        drug-containing layer is selected from the group consisting of        poly(hydroxyalkanoates) (PHAs), poly(ester amides) (PEAs),        poly(hydroxyalkanoate-co-ester amides), polyacrylates,        polymethacrylates, polycaprolactones, poly(ethylene        glycol)(PEG), poly(propylene glycol)(PPG), poly(propylene oxide)        (PPO), poly(propylene fumarate) (PPF), poly(D-lactide),        poly(L-lactide), poly(D,L-lactide), poly(meso-lactide),        poly(L-lactide-co-meso-lactide),        poly(D-lactide-co-meso-lactide),        poly(D,L-lactide-co-raeso-lactide), poly(D,L-lactide-co-PEG),        poly(D,L-lactide-co-trimethylene carbonate),        poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene        carbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG        (PolyActive(R)), PEG-PPO-PEG(Pluronic(R)), and PPF-co-PEG,        polycaprolactones, polyglycerol sebacate, polycarbonates,        biopolyesters, polyethylene oxide, polybutylene terephalate,        polydioxanones, hybrids, composites, collagen matrices with        grouth modulators, proteoglycans, glycosaminoglycans, vacuum        formed small intestinal submucosa, fibers, chitin, dexran and        mixtures thereof.    -   14. The drug eluting stent of embodiment 13, wherein the        drug-containing layer is selected from tyrosine derived        polycarbonates.    -   15. The drug eluting stent of embodiment 13, wherein the        drug-containing layer is selected from poly(β-hydroxyalcanoate)s        and derivatives thereof.    -   16. The drug eluting stent of embodiment 13, wherein the        drug-containing layer comprises a polylactide-co-glycolide 50/50        (PLGA).    -   17. The drug eluting stent of embodiment 1, wherein the        biocompatible base layer comprises at least one of poly n-butyl        methacrylate, PTFE PVDF-HFP,        poly(styrene-b-isobutylene-b-styrene), Parylene C, PVP, PEVA,        SBS, PC, or TiO2.    -   18. The drug eluting stent of embodiment 1, wherein the        biocompatible base layer comprises an electro-grafted polymeric        layer haying an interdigitated surface with the drug-containing        layer.    -   19. The drug eluting stent of embodiment 18, wherein the        electro-grafted polymeric layer has a thickness between 10 nm        and 1000 nm.    -   20. The drug eluting stent of embodiment 18, wherein the        electro-grafted polymeric layer comprises a monomer selected        from the group consisting of vinylics, epoxides, and cyclic        monomers undergoing ring opening polymerization and aryl        diazonium salts.    -   21. The drug eluting stent of embodiment 24, wherein the monomer        is further selected from the group consisting of butyl        methacrylate, methyl methacrylate, hydroxyethyl methacrylate,        epsilon caprolactone, and 4-aminophenyl diazonium tetrafluoro        borate.    -   22. A drug eluting stent, comprising:        -   a stent framework;        -   a biodegradable drug-containing layer;        -   a drug embedded in the drug-containing layer; and        -   a biocompatible base layer disposed over the stent framework            and supporting the drug-containing layer,        -   wherein the drug-containing layer is configured to            significantly dissolve between 45 days and 60 days after            implantation of the drug stent.    -   23. The drug eluting stent of embodiment 22, wherein the        drug-containing layer is formed from a plurality of polymers.    -   24. The drug eluting stent of embodiment 23, wherein one or more        polymers forming the drug-containing layer on a luminal side of        the stent and the drug-containing layer on a lateral side of the        stent degrade faster than one or more polymers forming the        drug-containing layers on an abluminal side of the stent.    -   25. The drug eluting stent of embodiment 22, wherein the stent        framework is fabricated from a single piece of metal, wire, or        tubing.    -   26. The drug eluting stent of embodiment 25, wherein the metal        comprises at least one of stainless steel, nitinol, tantalum,        cobalt-chromium MP35N or MP20N alloys, platinum. and titanium.    -   27. The drug eluting stent of embodiment 23, wherein the stent        framework is fabricated from a biodegradable material.    -   28. The drug eluting stent of embodiment 22, wherein the drug        comprises at least one of an antithrombogenic agent, an        anticoagulant, an antiplatelet agent, an antineoplastic agent,        an antiproliferative agent, an antibiotic, an anti-inflammatory        agent, a gene therapy agent, a recombinant DNA product, a        recombinant RNA product, a collagen, a collagen derivative, a        protein analog, a saccharide, a saccharide derivative, an        inhibitor of smooth muscle cell proliferation, a promoter of        endothelial cell migration, proliferation, and/or survival, and        combinations of the same.    -   29. The drug eluting stent of embodiment 22, wherein the drug        comprises sirolimus and/or a derivative or analog.    -   30. The drug eluting stent of embodiment 22, wherein the        drug-containing layer has a thickness between 5 and 12 μm.    -   31. The drug eluting stent of embodiment 22, wherein the        drug-containing layer is selected from the group consisting of        poly(hydroxyalkanoates) (PHAs), poly(ester amides) (PEAs),        poly(hydroxyalkanoate-co-ester amides), polyacrylates,        polymethacrylates, polycaprolactones, poly(ethylene        glycol)(PEG), poly(propylene glycol t(PPG). poly(propylene        oxide) (PPO), poly(propylene fumarate) (PPF), poly(D-lactide),        poly(L-lactide), poly(D,L-lactide), poly(meso-lactide),        poly(L-lactide-co-meso-lactide),        poly(D-lactide-co-meso-lactide),        poly(D,L-lactide-co-meso-lactide), poly(D,L-lactide-co-PEG),        poly(D,L-lactide-co-trimethylene carbonate),        poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene        carbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG        (PolyActive(R)), PEG-PPO-PEG(Pluronic(R)), and PPF-co-PEG,        polycaprolactones, polyglycerol sebacate, polycarbonates,        biopolyesters, polyethylene oxide, polybutylene terephalate,        polydioxanones, hybrids, composites, collagen matrices with        grouth modulators, proteoglycans, glycosaminoglycans, vacuum        formed small intestinal submucosa, fibers, chitin, dexran and        mixtures thereof.    -   32. The drug eluting stent of embodiment 31, wherein the        drug-containing layer is selected from tyrosine derived        polycarbonates.    -   33. The drug eluting stent of embodiment 31, wherein the        drug-containing layer is selected from poly(β-hydroxyalcanoate)s        and derivatives thereof.    -   34. The drug eluting stent of embodiment 31, wherein the        drug-containing layer comprises a polylactide-co-glycolide 50/50        (PLGA).    -   35. The drug eluting stent of embodiment 22, wherein the        biocompatible base layer comprises at least one of poly n-butyl        methacrylate, PTFE, PVDF-HFP,        poly(styrene-b-isobutylene-b-styrene), Parylene C, PVP, PEVA,        SBS, PC, or TiO2.    -   36. The drug eluting stent of embodiment 22, wherein the        biocompatible base layer comprises an electro-grafted polymeric        layer having an interdigitated surface with the drug-containing        layer.    -   37. The drug eluting stent of embodiment 36, wherein the        electro-grafted polymeric layer has a thickness between 10 nm        and 1000 nm.    -   38. The drug eluting stent of embodiment 36, wherein the        electro-grafted polymeric layer comprises a monomer selected        from the group consisting of vinylics, epoxides, and cyclic        monomers undergoing ring opening polymerization and aryl        diazonium salts.    -   39. The drug eluting stent of embodiment 38, wherein the monomer        is further selected from the group consisting of butyl        methacrylate, methyl methacrylate, hydroxyethyl methacrylate,        epsilon caprolactone, and 4-aminophenyl diazonium tetrafluoro        borate.    -   40. A method of using the stent according to any one of        embodiments 1 through 39, the method comprising implanting the        stent into a subject for the treatment of angiostenosis or to        prevent restenosis, thrombosis, tumor growth, angioma or,        obstruction of lacrimal gland.    -   41. The method of embodiment 40, wherein the stent is implanted        into a vessel.    -   42. The method of embodiment 41, wherein the vessel is the left        main coronary artery, circumflex artery, left anterior        descending coronary artery, an iliac vessel, a carotid artery,        or a neurovascular vessel.    -   43. A method of treatment, comprising: a step of delivering the        stent according to any one of embodiments 1 through 39 into a        lumen; a step of radially expanding the stent within the lumen;        and a step of eluting a drug from a drug coating layer in the        surface of the stent allowing the drug to act on the lumen and        or albumen surface.    -   44. A method of reducing, minimizing, or eliminating patient        risks associated with the implantation of a stent by using any        one of the stents according to any one of embodiments 1 through        39.    -   45. A method of fabricating a drug eluting stent, the method        comprising:        -   providing a stent framework; and        -   unevenly coating the stent framework with at least one            polymer mixed with at least one drug.    -   46. The method of embodiment 45, wherein unevenly coating        comprises coating the luminal and/or lateral sides of the stent        with a thinner coating than the coating of the abluminal side,        preferably wherein the coating that is thinner is a        drug-containing layer and/or a biocompatible base layer        underneath the drug-containing layer.    -   47. The method of embodiment 45, further comprising dissolving        at least one polymer and at least one drug to form the at least        one polymer mixed with at least one drug.    -   48. The method of embodiment 45, wherein unevenly coating the        stent framework comprises spray coating the stent framework with        the at least one polymer mixed with at least one drug.    -   49. The method of embodiment 46, wherein unevenly coating the        stent framework comprises rotating the stent framework during        spray coating to generate a centrifugal force.    -   50. The method of embodiment 49, wherein the centrifugal force        causes a greater thickness of the mixture on an abluminal side        of stent framework with respect to a luminal side of the stent        framework and a lateral side of the stent framework.    -   51. The method of embodiment 45, further comprising drying the        coated stent framework in a vacuum oven.    -   52. The method of embodiment 51, wherein the coated stent        framework is dried between 40° C. to 50° C.    -   53. The method of embodiment 48, wherein a flow of the spray is        24 μL/s or less    -   54. The method of embodiment 48, wherein a volume of the spray        is 192 μL/s or less.    -   55. The method of embodiment 48, wherein the spray coating is        performed at 0.3 bars pressure or less.    -   56. The method of embodiment 49wherein a speed of the rotation        of the stent is at least 2000 rpm.    -   57. The method of embodiment 48, wherein a distance between a        nozzle performing the spray coating and the stent framework is        6.5 mm or less.    -   58. The method of any of embodiments 45 to 57, further        comprising:        -   electro-grafting at least one polymer onto the stent            framework before spray coating the mounted framework.    -   59. The method of embodiment 58, further comprising:        -   baking the electro-grafted polymer at room temperature or            higher before spray coating the mounted framework.    -   60. The method of embodiment 59, wherein the baking is performed        in atmosphere conditions.    -   61. The method of embodiment 59, wherein the baking is performed        in nitrogen.    -   62. The method of embodiment 59, wherein the baking is performed        in vacuum.    -   63. A method of verifying long-term efficacy and safety of a        stent in human through implantation into a rabbit animal model,        the method comprising:        -   imaging the stent implanted into a rabbit model with at            least one of a scan electron microscope (SEM) or an Evans            Blue uptake between 90 days and 120 days after implantation            to verify that an endothelial layer of the vessel covers at            least 90% of a surface of the stent, and that the Evans blue            uptake of the endothelium covering the stent is less than            30%.    -   64. A method of reducing and/or eliminating the restenosis,        thrombosis or MACE of a blood vessel associated with the stent        implantation, comprising the steps of    -   a) suppressing the smooth muscle cell proliferation of the blood        vessel after the stent implantation within the first 30 days of        the stent implantation; and    -   b) achieving sufficient re-endothelialization of the blood        vessel within 3 months of the stent implantation such that        endothelium function restoration can be achieved within 12        months of the stent implantation.    -   65. The method of embodiment 64, wherein the vessel is a blood        vasculature vessel.    -   66. The method of embodiment 64, wherein the step of suppressing        the smooth muscle proliferation is achieved by controlled        release of a suitable drug from the implanted stent through        proper dosage and release curve.    -   67. The method of embodiment 66, wherein the drug is completely        released by 30 days after the stent implantation.    -   68. The method of embodiment 64, wherein the implanted stent has        a layer of biocompatible and biodegradable carrier materials to        promote the complete drug release within 30 days of        implantation.    -   69. The method of embodiment 64, wherein the biocompatible and        biodegradable carrier material is PLGA or PLA.    -   70. The method of embodiment 68, wherein the drug carrier layer        is completely disappeared within 60 days of implantation.    -   71. The method of embodiment 67, wherein the surface of the        implanted stent is smooth, or without significant obstacles for        the endothelial cell to grow upon, to reestablish the proper        interaction among the cells and to cover the stent strut        surface.    -   72. The method of embodiment 66, wherein the surface of the        stent is coated with polymer using electro- or chemical grafting        coating technology.    -   73. The method of embodiment 66, wherein the stent has a        thickness of about 80 um to 110 um.    -   74. The method of embodiment 73, wherein the stent thickness is        about 100 to 110 μm.    -   75. The method of embodiment 68, wherein the suitable drug is        selected from a group consisting of sirolimus, paclitaxel,        everolimus, biolimus, novolimus, tacrolimus, pimecrolimus and        zotarolimus.    -   76. The method of embodiment 66, wherein the suitable stent can        be a metal stent or a biodegradable stent.    -   77. The method of embodiment 66 wherein the suitable stent is a        polymeric stent, partially or completely biodegradable.    -   78. A method of predicting, long term stent efficacy and patient        safety after implantation of a drug eluting stent, the method        comprising assessing the percentage of functional restoration of        the endothelium coverage of the stent and/or blood vessel after        stent implantation in an animal model, wherein about complete        re-endothelialization at about 90 days post-stent implantation        is predictive of long term stent efficacy and patient safety        after stent implantation. For example, the assessment may        include using an animal model to assess the percentage of the        coverage, a thickness and permeability of the endothelial layer        and a structure of the endothelial layer. The structure may        include the type of tissue, for example, the tissue composition        in terms of smooth muscle cells, matrix, and endothelial cells.    -   79. The method of embodiment 78, wherein long term stent        efficacy comprises absence of significant restenosis of the        vessel at the area of stent implantation.    -   80. The method of embodiment 78, wherein patient safety        comprises absence of thrombosis of the vessel within 1 year        post-stent implantation. In some embodiments, the thrombosis may        be absent at 5 years post-stent implantation.    -   81. The method of embodiment 78, wherein patient safety        comprises significant absence of MACE within 1 year post-stent        implantation. In some embodiments, the absence of MACE may be at        5 years post-stent implantation.    -   82. The stent or the method according to any one of embodiments        1 through 81, wherein the uneven thickness of the        drug-containing layer is achieved by spray coating of the        drug-containing layer.    -   83. The stent or the method according to any one of embodiments        1 through 81, wherein the thinner portion of the drug-containing        layer releases the drug faster than the thicker portion of the        drug-containing layer, preferably within 10 to 20 days, wherein        about complete release of the drug from the drug-containing        layer occurs within 30 days of stent implantation.    -   84. Use of the stent according to any one of embodiments 1 to 39        in the manufacture of a medicament or a device for treating or        preventing a vascular disease, preferably angiostenosis or to        prevent restenosis, thrombosis, tumor growth, angioma or        obstruction of lacrimal gland.    -   85. The stent or the method according to any one of embodiments        1 to 83, wherein the stent framework comprises an 8 crest        design.    -   86. The stent or the method according to any one of embodiments        1 to 83, wherein the stent framework comprises a 10 crest        design.    -   87. The stent or the method according to any one of embodiments        1 to 83, wherein the stent framework comprises an 11 crest        design.    -   88. The stent or the method according to any one of embodiments        1 to 83, wherein the stent framework comprises a plurality of        stent poles having a wave design.    -   89. The stent or the method according to any one of embodiments        1 to 83, wherein the stent framework comprises a plurality of        single linking poles alternating between two linking poles and        three linking poles between stent poles in an axial direction.    -   90. The stent or the method according to any one of embodiments        1 to 83, wherein the stent framework comprises four linking        poles on a first end in an axial direction and comprises four        linking poles on a second end in the axial direction.    -   91. The stent or the method according to any one of embodiments        1 to 83, wherein a width of a crown is greater than a width of a        pole.    -   92. The stent according to any one of embodiments 1-39 and        85-91, wherein the stent is a non-stainless steel stent.    -   93. The stent according to embodiment 92, wherein the stent        comprises a cobalt-chromium alloy.    -   94. The method according to embodiment 46, wherein the coating        is designed for the thinner layer to release at least one drug        from the drug-containing layer faster than from the thicker        layer, preferably within 10-20 days, more preferably wherein        about complete release is achieved within 30 days of stent        implantation.    -   95. The method according to embodiment 94, wherein the        drug-containing layer comprises a drug or drugs that suppress        smooth muscle cell proliferation and/or promote endothelial cell        migration, proliferation, and/or survival after stent        implantation, preferably sirolimus.    -   96. The method according to embodiment 94, wherein the coating        is designed to promote functional re-endothelialization of the        stent within months of the stent implantation such that        endothelium function restoration can be achieved within 12        months of the stent implantation.    -   97. The method according to embodiment 94, wherein the coating        is designed to completely dissolve between 45 days and 60 days        of implantation.    -   98. The method according to any one of embodiments 46 and 94-98,        wherein the drug-containing layer comprises PLGA and the        biocompatible base layer, when present, comprises PBMA.    -   99. The method according to embodiment 78, where the percentage        of functional restoration of the endothelium coverage of the        stent and/or blood vessel in the patient is reasonably        predictable from a study in an animal model, preferably a rabbit        animal model.    -   100. The method according to embodiment 78 or 79, wherein the        percentage of functional restoration of the endothelium coverage        of the stent is assessed by SEM, Evan's Blue staining, OCT,        VE-Cadherin/P120 confocal staining colocalization, or a        combination of the same.    -   101. The method according to embodiment 78, wherein the stent is        implanted into a heart vessel.    -   102. The method according to embodiment 78 or 79, wherein the        stent is a stainless steel stent.    -   103. The method according to embodiment 78 or 79, wherein the        stent is a non-stainless steel stent.    -   104. The method according to embodiment 78 or 79, wherein the        stent comprises a cobalt chromium alloy.    -   105. The method according to any one of embodiments 78-89 and        99-104, wherein the stent is a drug-eluting stent.    -   106. The method according to embodiment 105, wherein the        drug-eluting stent comprises a drug or drugs that suppress        smooth muscle cell proliferation and, or promote endothelial        cell migration, proliferation, and/or survival after slept        implantation, preferably sirolimus.    -   107. The method according to embodiment 105, wherein the stent        is selected from any one of the stents according to any one of        embodiments 1-39 and 84-93.

BRIEF DESCRIPTION OF THE FIGURES

The drawings depict only example embodiments of the present disclosureand do not therefore limit its scope. They serve to add specificity anddetail.

FIG. 1A depicts a vessel 100 prior to implantation of a stent.

FIG. 1B depicts a vessel 150 after implantation of a stent.

FIG. 2 depicts a Xience Xpedition stent 60 days after implantationimaged using SEM. The SEM images depict partial strut coverage withuncovered areas confined to middle and distal region of the stent. Thepercentage of endothelial coverage above stent struts is about 50%.

FIG. 3 depicts a drug eluting stent, according to some embodiments ofthe present disclosure, 60 days after implantation imaged using SEM. TheSEM images depict a well-covered stent with few uncovered strutslocalized to the middle of the stent. The percentage of endothelialcoverage above stent struts is about 80%.

FIG. 4A depicts a Xience Xpedition stent 60 days after implantationimaged using gross images with Evans Blue uptake, in which the positivestained area was 41.8%.

FIG. 4B depicts a confocal microscope image of the Xience Xpeditionstent of FIG. 4A 60 days after implantation with tiling at 10× objectiveand with dual immunofluroescent staining of VE-Cadherin (red channel)and P120 (Endothelial p120-catenin) (green channel). The scale bar is 1mm.

FIG. 4C depicts a confocal microscope image of a region of the XienceXpedition stent of FIG. 4B 60 days after implantation with 20×objective, where the region had VE-Cadherin poorly expressed atendothelial borders, generally indicating poor barrier function.VE-Cadherin was red channel (555 nm), P120 was green channel (488 nm),and blue channel (405 nm) was DAPI counterstain. The scale bar is 50 μm.

FIG. 4D depicts a confocal microscope image of another region of theXience Xpedition stent of FIG. 4B with 20× objective, where the regionhad VE-Cadherin poorly expressed at endothelial borders, generallyindicating poor barrier function. VE-Cadherin was red channel (555 nm),P120 was green channel (488 nm), and blue channel (405 nm) was DAPIcounterstain. The scale bar is 50 μm. As depicted in FIGS. 4A-4D,endothelial coverage from both markers was 21.2% above the struts; and21.2% between the struts=21.2%.

FIG. 5A depicts a drug eluting stent, according to some embodiments ofthe present disclosure, 60 days after implantation imaged using grossimages with Evans Blue uptake, in which the positive stained area was35.7%.

FIG. 5B depicts a confocal microscope image of the drug eluting stent ofFIG. 5A 60 days after implantation with tilting at 10× objective andwith dual immunofluorescent staining of VE-Cadherin (red channel) andP120 (green channel). The scale bar is 1 mm.

FIG. 5C depicts a confocal microscope image of a region of the drugeluting stent of FIG. 5B 60 days after implantation with 20× objective,where the region had partially endothelial barrier functioned area.VE-Cadherin was red channel (555 nm), P120 was green channel (488 nm),and blue channel (405 nm) was DAPI counterstain. The scale bar is 50 μm.

FIG. 5D depicts a confocal microscope image of another region of thedrug eluting stent of FIG. 5B 60 days after implantation with 20×objective, where the region had VE-Cadherin poorly expressed atendothelial borders, generally indicating poor barrier function.VE-Cadherin was red channel (555 nm ), P120 was green channel (488 nm),and blue channel (405 nm) was DAPI counterstain. The scale bar is 50 μm.As depicted in FIGS. 5A-5D, endothelial rage from both markers was 36.8%above the struts, and 38.8% between the struts.

FIG. 6 depicts a Xience Xpedition stent 90 days after implantationimaged using SEM. The SEM images show partial stent coverage withuncovered areas mostly in the middle section. The percentage ofendothelial coverage above stent struts is about 70%.

FIG. 7 depicts a drug eluting stent, according to some embodiments ofthe present disclosure, 90 days after implantation imaged using SEM. TheSEM images show complete stent coverage. The percentage of endothelialcoverage above stent struts is about 99%.

FIG. 8A depicts a Xience Xpedition stent 90 days after implantationusing gross images with Evans Blue uptake, in which the positive stainedarea was 31.8%.

FIG. 8B depicts a confocal microscope image of the Xience Xpeditionstent of FIG. 8A 90 days after implantation with tiling at 10× objectiveand with dual immunofluroescent staining of VE-Cadherin (red channel)and P120 (green channel). The scale bar is 1 mm.

FIG. 8C depicts a confocal microscope image of a region of the XienceXpedition stent of FIG. 8B 90 days after implantation with 20×objective, where the region had evidence of competent endothelialbarrier function (that is, co-localized p120/VE-cadherin). VE-Cadherinwas red channel (555 nm), P120 was green channel (488 nm), and bluechannel (405 nm) was DAPI counterstain. The scale bar is 50 μm.

FIG. 8D depicts a confocal microscope image of another region of theXience Xpedition stent of FIG. 8B 90 days after implantation with 20×objective, where the region had VE-Cadherin poorly expressed atendothelial borders, generally indicating poor barrier function.VE-Cadherin was red channel (555 nm), P120 was green channel (488 nm),and blue channel (405 nm) was DAPI counterstain. The scale bar is 50 μm.As depicted in FIGS. 8A-8D, endothelial coverage from both markers was46.8% above the struts; and 46.1% between the struts.

FIG. 9A depicts a drug eluting stent, according to some embodiments ofthe present disclosure, 90 days after implantation imaged using grossimages with Evans Blue uptake, in which the positive stained area was6.4%.

FIG. 9B depicts a confocal microscope image of the drug eluting stent ofFIG. 9A 90 days after implantation with tilting at 10× objective andwith dual immunofluroescent staining of VE-Cadherin (red channel) andP120 (green channel). The scale bar is 1 mm.

FIG. 9C depicts a confocal microscope image of a region of the drugeluting stent of FIG. 9B 90 days after implantation with 20× objective,where the region had evidence of competent endothelial barrier function(that is, co-localized p120/VE-cadherin). VE-Cadherin was red channel(555 nm), P120 was green channel (488 nm), and blue channel (405 nm) wasDAPI counterstain. The scale bar is 50 μm.

FIG. 10 shows the drug release time frame of a XIENCE V stent and aXIENCE PRIME as about 120 days. The drug release time of ENDEAVORRESOLUTE (i.e., a stent according to some embodiments of the presentdisclosure) as about 180 days.

FIG. 11 shows the relative position of layers of a stent according tosome embodiments of the present disclosure. The luminal side (6) facesthe blood flow, and the abluminal side (8) faces or contacts the vesselwall.

FIG. 12A depicts a drug eluting stent, according to some embodiments ofthe present disclosure, 45 days after implantation imaged using EvansBlue uptake, in which the positive stained area was 78.57%.

FIG. 12B depicts a drug eluting stent 45 days after implantation usingEvans Blue uptake, in which the positive stained, area was 55.0%.

FIG. 12C depicts a drug eluting stent 45 days after implantation imagedusing Evans Blue uptake, in which the positive stained area was 56.79%.

FIG. 12D is a table summarizing the results of Evan's Blue update dataat 45 day from experiments done with a stent according to embodiments ofthe present disclosure (BuMA Supreme) and not according to the presentdisclosure (Xience and Synergy).

FIG. 13A depicts a drug eluting stent, according to some embodiments ofthe present disclosure, 45 days after implantation showing a confocalmicroscope image of a region of the drug eluting stent with 20×objective, where the region had evidence of competent endothelialbarrier function (that is, co-localized p120/VE-cadherin). VE Cadherinwas red channel (555 nm), P120 was green channel (488 nm), and bluechannel (405 nm) was DAPI counterstain.

FIG. 13B depicts a drug eluting stent 45 days after implantation showinga confocal microscope image of a region of the drug eluting stent with20× objective, where the region had evidence of competent endothelialbarrier function (that is, co-localized p120/VE-cadherin). VE Cadherinwas red channel (555 nm), P120 was green channel (488 nm), and bluechannel (405 nm) was DAPI counterstain.

FIG. 13C depicts a drug eluting stent 45 days after implantation showinga confocal microscope image of a region of the drug eluting stent with20× objective, where the region had evidence of competent endothelialbarrier function (that is, co-localized p120/VE-cadherin). VE Cadherinwas red channel (555 nm), P120 was green channel (488 nm), and bluechannel (405 nm) was DAPI counterstain.

FIG. 13D is a table summarizing the results of the VE-Cadherin/P120colocalization data at 45 days from experiments done with a stentaccording to embodiments of the present disclosure (BuMA Supreme) andnot according to the present disclosure (Xience and Synergy).

FIG. 14A depicts a drug eluting stent, according to some embodiments ofthe present disclosure, 90 days after implantation imaged using EvansBlue uptake, in which the positive stained area was 23.21%.

FIG. 14B depicts a drug eluting stent 90 days after implantation usingEvans Blue uptake, in which the positive stained area was 47.95%.

FIG. 14C depicts a drug eluting stent 90 days after implantation imagedusing Evans Blue uptake, in which the positive stained area was 41.79%.

FIG. 14D is a table summarizing the results of Evan's Blue update dataat 90 days from experiments done with a stent according to embodimentsof the present disclosure (BuMA Supreme) and not according to thepresent disclosure (Xience and Synergy).

FIG. 15A depicts a drug eluting stent, according to some embodiments ofthe present disclosure, 90 days after implantation showing a confocalmicroscope image of a region of the drug eluting stent with 20×objective, where the region had evidence of competent endothelialbarrier function (that is, co-localized p120/VE-cadherin). VE Cadherinwas red channel (555 nm), P120 was green channel (488 nm), and bluechannel (405 nm) was DAPI counterstain.

FIG. 15B depicts a drug eluting stent 90 days after implantation showinga confocal microscope image of a region of the drug eluting stent with20× objective, where the region had evidence of competent endothelialbarrier function (that is, co-localized p120/VE-cadherin). VE Cadherinwas red channel (555 nm), P120 was green channel (488 nm), and bluechannel (405 nm) was DAPI counterstain.

FIG. 15C depicts a drug eluting stent 90 days after implantation showinga confocal microscope image of a region of the drug eluting stent with20× objective, where the region had evidence of competent endothelialbarrier function (that is, co-localized p120/VE-cadherin). VE Cadherinwas red channel (555 nm), P120 was green channel (488 nm), and bluechannel (405 nm) was DAPI counterstain.

FIG. 15D is a table summarizing the results of the VE-Cadherin/P120colocalization data at 90 days from experiments done with a stentaccording to embodiments of the present disclosure (BuMA Supreme) andnot according to the present disclosure (Xience and Synergy).

DETAILED DESCRIPTION

The present disclosure relates to drug eluting stents, methods of makingand using the chug eluting stents, as well as methods for predictinglong term stent efficacy and patient safety after implantation of adrug-eluting stent. According to some embodiments of the presentdisclosure, the drug eluting steal (1) comprises four parts: a stentframework (2), a drug-containing layer (3), a drug (4), and abiocompatible base layer (5). In one embodiment, the stent may be madewith stainless steel. In another embodiment, the stent may be made ofCoCr alloy. In one embodiment, the stent has a between 80-120 um. Thedrug-containing layer may be formed of PLGA, and the biocompatible baselayer may be formed of PBMA. The biocompatible base layer may be formedusing an electrografting process.

The Stent Framework:

Stents are typically composed of a scaffold or scaffolding that includesa pattern or network of interconnecting structural elements or struts,formed from wires, tubes, or sheets of material rolled into acylindrical shape. This scaffold gets its name because it physicallyholds open and, if desired, expands the wall of a passageway in apatient. Typically, stents are capable of being compressed or crimpedonto a catheter so that they can be delivered to and deployed at atreatment site. Delivery includes inserting the stent through smalllumens using a catheter and transporting it to the treatment site.Deployment includes expanding the stent to a larger diameter once it isat the desired location.

A stent framework (2) may be fabricated from a single (or more) piece(s)of metal or wire or tubing, including the 3D printing and laser cutting(e.g., starting from a wire). For example, the stent framework may benon-stainless steel or comprise stainless steel, nitinol, tantalum,cobalt-chromium (e.g., MP35N or MP20N alloys), platinum, titanium,suitable biocompatible alloys, other suitable biocompatible materials,and/or combinations thereof. In some embodiments, the stent is anon-stainless steel stent. In other embodiments, the stent framework maybe fabricated from a metallic material or an alloy such as, but notlimited to. Cobalt chromium alloy (ELGILOY), stainless steel (316L),high nitrogen stainless steel e.g., BIODUR 108, cobalt chrome alloyL-605, ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium or combinations thereof. “MP35N”and “MP20N” are trade names for alloys of cobalt, nickel, chromium andmolybdenum available from Standard Press Steel Co., Jenkintown, Pa.“MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10%molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium,and 10% molybdenum.

In other embodiments, the stent framework (2) may be fabricated from oneor more plastics, for example, polyurethane, teflon, polyethylene, orthe like. In such embodiments, the stent framework (2) may befabricated, for example, using 3-D printing.

The stent framework (2) may form a mesh. Accordingly, the stentframework (2) may expand upon implantation, either from external forcessuch as from a balloon catheter and/or from internal forces such asexpansion of the mesh caused by increased temperature within the vessel.Upon expansion, the stent framework (2) may hold the vessel open.

In some embodiments, the stent framework (2) may be biodegradable. Inorder to effect healing of a diseased blood vessel, the presence of thestent is necessary only for a limited period of time, as the arteryundergoes physiological remodeling over time after deployment. Thedevelopment of a bioabsorbable stent or scaffold could obviate thepermanent metal implant in the vessel, allow late expansive luminal andvessel remodeling, and leave only healed native vessel tissue after thefull resorption of the scaffold. Stents fabricated from bioresorbable,biodegradable, bioabsorbable, and/or bioerodable materials such asbioabsorbable polymers can be designed to completely absorb only afteror some time after the clinical need for them has ended. Consequently, afully bioabsorbable stent can reduce or eliminate the risk of potentiallong-term complications and of late thrombosis, facilitate non-invasivediagnostic MRI/CT imaging, allow restoration of normal vasomotion, andprovide the potential for plaque regression. For example, the sentframework (2) may be fabricated from chitosan, magnesium alloy,polylactic acid, polycarbonate poylmers, salicylic acid polymers, and/orcombinations thereof. Advantageously, a biodegradable stent framework(2) may allow for the vessel to return to normalcy after a blockage hasbeen cleared and flow restored by the stent (1). The term“biodegradable” as used herein is interchangeable with the terms“bioabsorbable” or “bioerodable”, and generally refers to polymers orcertain specific alloys, such as magnesium alloy, that are capable ofbeing completely degraded and/or eroded when exposed to bodily fluidssuch as blood and can be gradually resorbed, absorbed, and/or eliminatedby the body. The processes of breaking down and absorption of thepolymer in a stent can be caused by, for example, hydrolysis andmetabolic processes.

“A biodegradable stent” is used herein to mean a stent made frombiodegradable polymers. Additional representative examples of polymersthat may be used for making a biodegradable stent include, but are notlimited to, poly(N-acetylglucosamine) (chitin), chitosan,poly(hydroxyvalerate), poly(lactide-coglycolide), poly(hydroxybutyrate),poly(hydroxybutyrateco-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(glycolide), poly(L-lactic acid),poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide),poly(caprolactone), poly(trimethylene carbonate), polyester amide,poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters)(e.g. PEO/PLA), polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers otherthan polyacrylates, vinyl halide polymers and copolymers (such aspolyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether),polyvinylidene halides (such as polyvinvlidene chloride),polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such aspolystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitridestyrene copolymers, ABS resins, polyamides (such as Nylon66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayontriacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose. Another type of polymer based on polylacticacid) that can be used includes graft copolymers, and block copolymers,such as AB block-copolymers (“diblock-copolymers”) or ABAblock-copolymers (“triblock-copolymers”), or mixtures thereof.

Additional representative examples of polymers that may be suited foruse in fabricating a biodegradable stent include ethylene vinyl alcoholcopolymer (commonly known by the generic name EVOI-I or by the tradename EVAL), poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluororpropene) (e.g., SOLEF 21508, available fromSolvay Solexis PVDF, Thorofare, N.J.), polyvinylidene fluoride(otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol. The properties and usages of these biodegradable polymers areknown in the art, for example, as disclosed in U.S. Pat. No. 8,017,144and U.S. application publication No. 2011/0,098,803.

In some aspects, a biodegradable stent as described herein may be madefrom polylactic acid (PLA), polyglycolic acid (PGA),poly(D,L-lactide-co-glycolide), polycaprolactone, or copolymers thereof.

In some aspects, a biodegradable stent as described herein may be madefrom polyhydroxy acids, polyalkanoates, polyanhydrides,polyphosphazenes, polyetheresters, polyesteramides, polyesters, andpolyorthoesters.

In some preferable aspects, a biodegradable stent as described hereinmay be made from chitosan, collagen, elastin, gelatin, fibrin glue, orcombinations thereof.

“Chitosan based stent”, “chitosan stent” as described herein mean thatthe major component of a stent comes from chitosan. For example, achitosan based stent as described herein may contain chitosan at leastin an amount of over 50%, or over 60%, or over 70%, or over 80% weightpercentage of the total stent weight. Even more particularly, a chitosanbased stent as described herein may have the chitosan content in anamount of between about 70% and about 85% weight percentage of the totalchitosan stent.

A chitosan based stent as described herein may also be coated with apolymer layer in order to adjust degradation times. For example, achitosan based stent as described herein may be dip-coated with asolution of poly(D,L-lactide-co-glycolide) in acetone.

A chitosan based stent may also be coated with a layer of bariumsulfate, by dipping the stents into an aqueous suspension of bariumsulfite. in some aspects, the weight of the coated barium sulfate may bein an amount of between about 15 and between about 30 weight percentageof the total weight of the stent. Additionally, a chitosan stent may beperforated.

The stent designed according to the criteria of this disclosure may be acoronary stent, a vascular stent, or any other drug-containingimplantable devices for vascular system as well any medical device thatis effective in lowering the restenosis and thrombosis rates in asustainable manner to secure patient safety in the long term.

In one embodiment, a thinner stent is used. However, the stent strutshould have enough thickness which will ensure the stent structurestability, without the risk of breaking over time. As an example, thethickness of the stent for 316L stainless steel stent is about 100 to110 um, and for the CoCr stent is about 80 um.

The Drug-Containing Layer:

The disclosure provides that there is a window of opportunity forvascular restoration of the endothelium after the implantation of astent into a heart vessel in terms of patient safety and stent efficacy.In one embodiment, it is necessary for the re-endothelialization of thestent to be sufficiently accomplished and proper structural foundationof the endothelium or alignment of the endothelial cells is establishedwithin the window time period disclosed herein such that functionalrestoration of the endothelium coverage of the stent can be obtained andrestenosis and/or thrombosis be significantly prevented or reduced. Inone embodiment, sufficient re-endothelialization of the stent/vascularwall is obtained within the first 2-3 months such that the vascularendothelial function restoration can be achieved within 12 months. Thesufficiency of the restoration of the endothelium can be determined byany means known in the industry. In animal models, this can be measuredby methods that include Evans-blue staining (the presence of thestaining is a negative marker for desirable endothelial cell layerfunctioning), VE-Cadherin/p120 staining (the presence of good overlap instaining is a positive marker of desirable endothelial cell layerfunctioning), and others. In vivo, it may for example be measured byneointimal coverage of the surface of stent struts, and neointimalthickness as measured by OCT methods known in art at different timepoints. For example, a thickness below a first threshold may beindicative that a sufficient foundation structure has not formed, whichwill result in less sufficient restoration of the function of theendothelial layer, while a thickness above a second, higher thresholdmay be indicative of a ratio of smooth muscle cells to endothelial cellsthat is too high, sometimes it is a good indication for overproliferation of the smooth muscle cells.

In one embodiment, endothelium restoration means that the rightconnection among the endothelial cells is re-established, and thebiological function of the Endothelium is restored over the surface ofthe stent or along the vessel wall/neointima. Endothelium refers to afunctional endothelial layer. Vascular functional restoration can bemeasured by any means known in the industry. For example, it can bemeasured by neointimal coverage of the surface of stent struts, andneointimal thickness as measured by OCT (e.g., one to three months) orother methods known in art at different time points (e.g., SEMexamination of the stent coating). Other means that measure the functionof the endothelium can also be used (Evan's blue (e.g., at 30, 60, and90 days; should not stain the endothelial layer), VE cadherin/P120confocal microscopy staining overlap is desirable).

In one embodiment, the drug eluting stent, is designed in such way thatit can achieve complete drug release within 30 days, and substantialneointimal coverage at 3 months.

For the purposes of this disclosure, “complete drug release” from thestent (drug-containing layer) means release of from about 95% to about100% of the drug, preferably from about 95%- to about 96%, from about96%- to about 97%, from about 97%- to about 98%, from about 98% to about99%, and from about 99%- to about 100% of the drug. Drug release isassessed in animal models (e.g., rabbit model) or in vitro models thatare understood by one of ordinary skill in the art, as predictable ofdrug release in the subject in which the stent of the disclosure isimplanted. In one embodiment, “completely released” refers to a level atwhich the drug remaining is below detectable level and/or below atherapeutic level.

For the purposes of this disclosure, the drug-containing layer is saidto have “completely dissolved” (also referred to as bio-degraded) whenfrom about 95% to about 100% of the drug-containing layer, preferablyfrom about 95%- to about 96%, from about 96%- to about 97%, from about97%- to about 98%, from about 98% to about 99%, and from about 99%- toabout 100% of the drug-containing layer has dissolved (also referred toas bio-degraded) from the stent. Drug-containing layer dissolution (alsoreferred to as bio-degradation) from the stent is assessed in animalmodels (e.g., rabbit model) or in vitro models that are understood byone of ordinary skill in the art as predictable of the drug-containinglayer dissolution (also referred to as bio-degradation) from the stentin the subject in which the stent of the disclosure is implanted. In oneembodiment, “completely dissolved” refers to a level at which thematerial remaining is below a detectable level.

A drug-containing layer (3) may be made from polymers and may comprise alayer or layers covering all or part of the stent surface. Furthermore,a drug-containing layer (3) may be capable of hosting a drug (4) andreleasing the drug (4) in a sustained manner. Examples of the polymersusing in drug-containing layer (3) may include, but are not limited to,poly(hydroxyalkanoates) (PHAs), poly(ester amides) (PEAs),poly(hydroxyalkanoate-co-ester amides), polyacrylates,polymethacrylates, polycaprolactones, poly(ethylene glycol)(PEG),poly(propylene glycol)(PPG), poly(propylene oxide) (PPO), poly(propylenefumarate) (PPF), poly(D-lactide), poly(L-lactide), poly(D,L-lactide),poly(meso-lactide), poly(L-lactide-co-meso-lactide),poly(D-lactide-co-meso-lactide), poly(D,L-lactide-co-meso-lactide),poly(D,L-lactide-co-PEG), poly(D,L-lactide-co-trimethyiene carbonate),poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylenecarbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG(PolyActive®), PEG-PPO-PEG(Pluronic®), and PPF-co-PEG,polycaprolactones, polyglycerol sebacate, polycarbonates, biopolyesters,polyethylene oxide, polybutylene terephalate, polydioxanones, hybrids,composites, collagen matrices with grouth modulators, proteoglycans,glycosaminoglycans, vacuum formed small intestinal submucosa, fibers,chitin, dexran, and/or mixtures thereof.

The rate of degradation of the drug-containing polymer layer isgenerally determined by its composition. One of ordinary skill in theart may select one or more polymers using a standard PK animal test toconfirm that the polymer(s) degrade between 45 and 60 days afterimplantation. In addition, a manufacturer of the polymer or thepolymeric matrix may provide the degradation performance of thedrug-containing polymer, e.g., the degradation curve. One of ordinaryskill in the art may derive the rate of degradation of thedrug-containing polymer(s) from the degradation performance and selectthe polymer(s) based on the rate of degradation.

In one embodiment, the drug-containing layer (3) may have a thicknessbetween 1 and 200 μm, e.g., between 5 and 12 μm. In one embodiment, thedrug-containing layer has a thickness between 3.5-10 μm. In oneembodiment, the thickness of the abluminal side is between 1.5-200 μmand the thickness of the luminal side is between 1-66 μm.

In certain aspects, the drug-containing layer (3) may have an unevencoating thickness. For example, the coating thickness of the luminalside (6) and the lateral side (7) may be thinner than the abluminal side(8) of the stent. In one embodiment, a coating thickness ratio betweenthe luminal side (6) and the abluminal side (8) may range from 2:3 to1:7. Similarly, the coating thickness ratio between the lateral side (7)and the abluminal side (8) may range from 2:3 to 1:7. Accordingly, thedrug release on the luminal side (6) and the lateral side (7) may befaster than the abluminal side (8). The faster release of the ding onthe luminal side (6) and the lateral side (7) may enable fasterrestoration of endothelia layers on the luminal side (6) and the lateralside (7) compared with the abluminal side (8). In another embodiment,the coating thickness ratio between the luminal side (6) and theabluminal side (8) may be 1:1. Ranges provided herein are understood tobe shorthand for all of the values within the range. For example, arange of 1 to 10 is understood to include any number, combination ofnumbers, or sub-ranges such as 1, 1.5, 2.0, 2.8, 3.90, 4, 5, 6, 7, 8, 9,and 10.

In some embodiments, the drug-containing layer (3) may be coated on theabluminal side (8) of the stern only. In such embodiments, the lack ofdrug release from the luminal side (6) and the lateral side (7) mayenable the early restoration of endothelia layers on the luminal side(6) and the lateral side (7). In other embodiments, the drug releasefrom the luminal side (6) and the lateral side (7) may be less than 15days, or 10-20 days, which may enable the early restoration ofendothelial layers on the luminal side (6) and the lateral side (7).

Moreover, in such embodiments, the degradation of polymer on the luminalside (6) and the lateral side (7) may be faster than the degradation ofpolymer on the abluminal side (8). For example, the polymer of theluminal side (6) and the lateral side (7) may comprise PLGA, and thepolymer of the abluminal side (8) may comprise PLA. Generally, thedegradation of PLGA is faster than PLA, and this information can beeasily accessed from the polymer manufacturer.

In some embodiments, sometimes advantageously, a 30-day drug (4) releasetime frame and a 45-to-60-day drug-containing coating (3)bio-degradable/dissolution time frame may enable the functionalrestoration of endothelial layers. Within the time frame mentionedabove, the restoration of the functional EC layer may be sufficientlycompleted in 90 days as measured in rabbit animal model. Then it mayenable the long-term safety of the drug eluting stent in human. In oneembodiment, the stent is unevenly coated by the drug containing layer,producing a thinner drug coating on the luminal or luminal side of thestent, which enables the drug to disappear from the stent between 10 to20 days.

The drug-containing coating may soften, dissolve or erode from the stentto elute at least one bioactive agent. This elution mechanism may bereferred to as surface erosion where the outside surface of thedrug-polymer coating dissolves, degrades, or is absorbed by the body; orbulk erosion where the bulk of the drug-polymer coating biodegrades torelease the bioactive agent. Eroded portions of the drug-polymer coatingmay be absorbed by the body, metabolized, or otherwise expelled.

The drug-containing coating may also include a polymeric matrix. Forexample, the polymeric matrix may include a caprolactone-based polymeror copolymer, or various cyclic polymers. The polymeric matrix mayinclude various synthetic and non-synthetic or naturally occurringmacromolecules and their derivatives. The polymer is advantageouslyselected in the group consisting of one or more biodegradable polymersin varying combinations, such as polymers, copolymers, and blockpolymers. Some examples of such biodegradable (also bio-resorbable orelse bioabsorbable) polymers include polyglycolides, polylactides,polycaprolactones, polyglycerol sebacate, polycarbonates e.g. tyrosinederived, biopolyesters such as poly(β-hydroxyalcanoate)s (PHAs) andderived compounds, polyethylene oxide, polybutylene terepthalate,polydioxanones, hybrids, composites, collagen matrices with growthmodulators, proteoglycans, glycosaminoglycans, vacuum formed SIS (smallintestinal submucosa), fibers, chitin, and dextran. Any of thesebiodegradable polymers may be used alone or in combination with these orother biodegradable polymers in varying compositions. The polymericmatrix preferably includes biodegradable polymers such as polylactide(PLA), polyglycolic acid (PGA) polymer, poly (e-caprolactone) (PCL),polyacrylates, polymethacryates, or other copolymers. The pharmaceuticaldrug may be dispersed throughout the polymeric matrix. Thepharmaceutical drug or the bioactive agent may diffuse out from thepolymeric matrix to elute the bioactive agent. The pharmaceutical drugmay diffuse out from the polymeric matrix and into the biomaterialsurrounding the stent. The bioactive agent may separate from within thedrug-polymer and diffuse out from the polymeric matrix into thesurrounding biomaterial. In a further embodiment the drug coatingcomposition may be fashioned using the drug42-Epi-(tetrazolyl)-Sirolimus, set forth in U.S. Pat. No. 6,329,386assigned to Abbott Laboratories, Abbott Park, Ill. and dispersed withina coating fashioned from phosphorylcholine coating of BiocompatiblesInternational P.L.C. set forth in U.S. Pat. No. 5,648,442.

The polymeric matrix of the drug-containing layer may be selected toprovide a desired elution rate of the drug/bioactive agent. Thepharmaceutical drugs may be synthesized such that a particular bioactiveagent may have two different elution rates. A bioactive agent with twodifferent elution rates, for example, would allow rapid delivery of thepharmacologically active drug within twenty-four hours of surgery, witha slower, steady delivery of the drug, for example, over the next two tosix months. The electro-grafted primer coating may be selected to firmlysecure the polymeric matrix to the stent framework, the polymeric matrixcontaining the rapidly deployed bioactive agents and the slowly elutingpharmaceutical drugs.

In some embodiments, a drug (4) may be encapsulated in thedrug-containing layer (3) using a microbead, microparticle ornanoencapsulation technology with albumin, liposome, ferritin or otherbiodegradable proteins and phospholipids, prior to application on theprimer-coated stent.

The Drug or Bioactive Agent

By way of example, drug (4) may include, for example, antithrombogenicagent, an anticoagulant, an antiplatelet agent, an antineoplastic agent,an antiproliferative agent, an antibiotic, an anti-inflammatory agent, agene therapy agent, a recombinant DNA product, a recombinant RNAproduct, a collagen, a collagen derivative, a protein analog, asaccharide, a saccharide derivative, an inhibitor of smooth muscle cellproliferation, a promoter of endothelial cell migration, proliferation,and/or survival, and combinations of the same. In one embodiment, thedrug is an anti-angiogenic drug. In another embodiment, the drug is anangiogenic drug. In some embodiments, the drug/bioactive agent maycontrol cellular proliferation. The control of cell proliferation mayinclude enhancing or inhibiting the growth of targeted cells or celltypes. In some embodiments, the cells are vascular smooth muscle cells,endothelial cells, or both. In some embodiments, the drug suppresses theproliferation of smooth muscle cells and/or promotes the proliferationof endothelial cells.

More broadly, drug (4) may be any therapeutic substance that provides atherapeutic characteristic for the prevention and treatment of diseaseor disorders. For example, an antineoplastic agent may prevent, kill, orblock the growth and spread of cancer cells in the vicinity of thestent. In another example, an antiproliferative agent may prevent orstop cells from growing. In yet a further example, an antisense agentmay work at the genetic level to interrupt the process by whichdisease-causing proteins are produced. In a fourth example, anantiplatelet agent may act on blood platelets, inhibiting their functionin blood coagulation. In a fifth example, an antithrombogenic agent mayactively retard blood clot formation. According, to a sixth example, ananticoagulant may delay or prevent blood coagulation with anticoagulanttherapy, using compounds such as heparin and coumarins. In a seventhexample, an antibiotic may kill or inhibit the growth of microorganismsand may be used to combat disease and infection. In an eighth example,an anti-inflammatory agent may be used to counteract or reduceinflammation in the vicinity of the stent. According to a ninth example,gene therapy agent may be capable of changing the expression of aperson's genes to treat, cure or ultimately prevent disease. Inaddition, an organic drug may be any small-molecule therapeuticmaterial, and, similarly, a pharmaceutical compound may be any compoundthat provides a therapeutic effect. A recombinant DNA product or arecombinant RNA product may include altered DNA or RNA genetic material.In another example, bioactive agents of pharmaceutical value may alsoinclude collagen and other proteins, saccharides, and their derivatives.For example, the bioactive agent may be selected to inhibit vascularrestenosis, a condition corresponding to a narrowing or constriction ofthe diameter of the bodily lumen where the stent is placed

Alternatively or concurrently, the bioactive agent may be an agentagainst one or more conditions, including, but not limited to, coronaryrestenosis, cardiovascular restenosis, angiographic restenosis,arteriosclerosis, hyperplasia, and other diseases and conditions. Forexample, the bioactive agent may be selected to inhibit or preventvascular restenosis, a condition corresponding to a narrowing orconstriction of the diameter of the bodily lumen where the stent isplaced. The bioactive agent may alternatively or concurrently controlcellular proliferation. The control of cell proliferation may includeenhancing or inhibiting the growth of targeted cells or cell types.

Examples of antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax™ (bivalirudin, Biogen, Inc., Cambridge, Mass.) calciumchannel blockers (such as nifedipine), colchicine, fibroblast growthfactor (FGF) antagonists, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin (an inhibitor of HMG-CoA reductase, acholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc.,Whitehouse Station, N.J.), monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide, nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1 1-oxyl (4-amino-TEMPO),estradiol, dietary supplements such as various vitamins, andcombinations thereof.

In some embodiments, the bioactive agent may include podophyllotoxin,etoposide, camptothecin, a camptothecin analog, mitoxantrone, Sirolimus(rapamycin), everolimus, zotarolimus, Biolimus A9, myolimus,deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, novolimus,zotarolimus (ABT-578), 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxypropyl(rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazolylrapamycin,40-epi-(N1-tetrazolyl)-rapamycin, and their derivatives or analogs.Podophyllotoxin is generally an organic, highly toxic drug that hasantitumor properties and may inhibit DNA synthesis. Etoposide isgenerally an antineoplastic that may be derived from a semi-syntheticform of podophyllotoxin to treat monocystic leukemia, lymphoma,small-cell lung cancer, and testicular cancer. Camptothecin is generallyan anticancer drug that may function as a topoisomerase inhibitor.Related in structure to camptothecin, a camptothecin analog, such asaminocamptothecin, may also be used as an anticancer drug. Mitoxantroneis an anticancer drug generally used to treat leukemia, lymphoma, andbreast cancer. Sirolimus is a medication that generally interferes withthe normal cell growth cycle and may be used to reduce restenosis. Thebioactive agent may alternatively or concurrently include analogs andderivatives of these agents. Antioxidants may be used in combinationwith or individually from the examples above for their antirestoneticproperties and therapeutic effects.

The anti-inflammatory agent can be a steroidal anti-inflammatory agent,a nonsteroidal anti-inflammatory agent, or a combination thereof. Insome embodiments, anti-inflammatory drugs include, but are not limitedto, alclofenac, alclometasone dipropionate,. algestone acetonide, alphaamylase, amcinafal, amcinafide, amfenac sodium, amiprilosehydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazidedisodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetasol propionate, clobetasone butyrate, clopirac, cloticasonepropionate, cormethasone acetate, cortodoxone, deflazacort, desonide,desoximetasone, dexamethasone dipropionate, diclofenac potassium,diclofenac sodium, diflorasone diacetate, diflumidone sodium,diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinomide,endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate,felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal,fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid,flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortinbutyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen,fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasolpropionate, halopredone acetate, ibufenac, ibuprofen, ibuprofenaluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacinsodium, indoprofen, indoxole, intrazole, isoflupredone acetate,isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam,loteprednol etabonate, meclofenamate sodium, meclofenamic acid,meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone,methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone,piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen,prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazolecitrate, rimexolone, romazarit, salcolex, salnacedin, salsalate,sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap,tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylicacid), salicylic acid, corticosteroids, glucocorticoids, tacrolimuspimecorlimus, prodrugs thereof, co-drugs thereof, and combinationsthereof.

For the removal of blood clots and thrombus, examples of therapeuticagents may include (i) tissue plasminogen activator, tPA, BB-10153, rTPAUrokinease, Streptokinase, Alteplase and Desmoteplase, (ii) antiplateletagents such as aspirin. Clopidorgel and Ticclopidine, and (iii)GIIb/IIIa inhibitors, such as Abciximab, Tirofiban and Eptifibatide.

The dosage or concentration of the drug required to produce a favorabletherapeutic effect should be less than the level at which the drugproduces toxic effects and greater than the level at whichnon-therapeutic results are obtained. This applies to anantiproliferative agent, a prohealing agent, or any other active agentincluded in any of the various embodiments of the invention.Therapeutically effective dosages can also be determined from anappropriate clinical study, such as but not limited to, a Phase II orPhase III study. Effective dosages can also be determined by theapplication of an appropriate pharmacokinetic-pharmacodynamic model inhuman, or other animals. Standard pharmacological test procedures todetermine dosages are understood by one of ordinary skill in the art. Insome embodiments, the stent has a drug content of from about 5 μg toabout 500 μg. In some embodiments, the stent has a drug content of fromabout 100 μg to about 160 μg. In one embodiment, the content of the drugin the drug-containing layer is from 0.5-50% by weight. In otherembodiments, the drug-containing layer comprises from 0.5-10 ug/mm2 ofdrug (e.g., 1.4 ug/mm2).

When the drug eluting stent (1) is implanted into the human body vessel,the drug (4) may be released from drug-containing coating (3) within 30days. Alternatively, for example, the drug may be released within 45days, 60 days, or 120 days. The rate of drug release may be measuredthrough a standard PK animal study, in which the fluid samples andtissues and the stents are extracted from animals at selected timepoints, and the concentration of drugs measured to best design theproperties of the stent. These animal studies are reasonably predictiveof what happens in humans, as well understood by one of ordinary skillin the art. Moreover, in embodiments where the drug-containing coating(3) is made from a bio-degradable or bio-absorbable polymer, the polymermay be bio-degraded or bio-absorbed between 45 days and 60 days. Forexample, 50:50 PLGA (as described in Example 1 below) may exhibit invivo degradation time of about 60 days.

The Biocompatible Base Layer (5)

Over the stent framework (2), and underneath the drug-containing layer(3), a biocompatible base layer (5) may be formed, which may have abetter biocompatible surface than the stent framework (2). For example,compared with a bare metal surface of the framework, the biocompatiblesurface of biocompatible base layer (5) may enable the early functionalrestoration of endothelia layers on a luminal side (6) and a lateralside (7) of the stent, which may result in a faster rate of migrationand replication of the EC compared with a bare metal surface.

The biocompatible base layer (5) may be made from poly-n-butylmethacrylate, PVDF-HFP poly(styrene-b-isobutylene-b-styrene), ParyleneC, PVP, PEVA, SBS, PC, TiO2 or any material has good biocompatibility(or combinations thereof). In one embodiment, the base layer comprisesor consists essentially of PBMA.

Other Materials

All embodiments may also include additional components such as, but notlimited to, lubricating agents, fillers, plasticizing agents,surfactants, diluents, mold release agents, agents which act as activeagent carriers or binders, anti-tack agents, anti-foaming agents,viscosity modifiers, potentially residual levels of solvents, andpotentially any other agent which aids in, or is desirable in, theprocessing of the material, and/or is useful, or desirable, as acomponent of the final product, or if included in the final product.

Methods of Using the Stents:

In one embodiment, a stent s a medical device used for improving astenosed region or an occluded region in a lumen in an organism such asa blood vessel, a bile duct (often, plastic stents) a trachea, anesophagus, an airway, an urethra or the like. Stents are inserted intothese and other hollow organs to ensure that these hollow organsmaintain sufficient clearance.

One use for medical stents is to expand a body lumen, such as a bloodvessel, which has contracted in diameter through, for example, theeffects of lesions called atheroma or the occurrence of canceroustumors. Atheroma refers to lesions within arteries that include plaqueaccumulations that can obstruct blood flow through the vessel. Overtime, the plaque can increase in size and thickness and can eventuallylead to clinically significant narrowing of the artery, or even completeocclusion. When expanded against, the body lumen, which has contractedin diameter, the medical stents provide a tube-like support structureinside the body lumen. Stents also can be used for the endovascularrepair of aneurysms, an abnormal widening or ballooning of a portion ofa body lumen which can be related to weakness in the wall of the bodylumen.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy usesmedicated stents to locally administer a therapeutic substance. Thetherapeutic substance can also mitigate an adverse biological responseto the presence of the stent. A medicated stent (i.e., a stentcomprising a drug) may be fabricated by the methods disclosed herein toinclude a polymeric carrier that includes an active or bioactive agentor drug.

In one embodiment, the stent is used in methods of treating a disease ordisorder in a subject. Examples of disease or disorders where the stentcan be used include diseases of the vasculature (heart disease,thrombosis, tumors, angioma, obstruction of lacrimal gland and otherdiseases of a lumen. The stent can be used for percutaneous coronaryintervention (PCI) as well as in peripheral applications, such as thesuperficial femoral artery (SPA). In some embodiments, the stent can beused for the treatment of angiostenosis or to prevent restenosis, byutilizing a cell proliferation-suppressing agent such as cytostatic(e.g.,. paclitaxel) or immunosuppressant as the drug. In someembodiments, a ureteral stent of the disclosure is introduced into thekidney and/or the bladder of a subject.

As used herein, the term “subject” refers to human and non-humananimals, including veterinary subjects. The term “non-human animal”includes all vertebrates, e.g., mammals and non-mammals, such asnon-human primates, mice, rabbits, sheep, dog, cat, horse, cow,chickens, amphibians, and reptiles. In a preferred embodiment, thesubject is a human and may be referred to as a patient.

As used herein, the terms “treat,” “treating” or “treatment” refers,preferably, to an action to obtain a beneficial or desired clinicalresult including, but not limited to, alleviation or amelioration of oneor more signs or symptoms of a disease or condition, diminishing theextent of disease, stability (i.e., not worsening) state of disease,amelioration or palliation of the disease state, diminishing rate of ortime to progression, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival in the absence of treatment.Treatment does not need to be curative.

Methods of Introducing the Stent into the Subject

In one embodiment, the stent is introduced into the subject body via acatheter, or by implantation. In other embodiments, the stent isintroduced by balloon catheter

The terms “inserting a stent”, “delivering a stent”, “placing a stent”,“employing a stent”, and similar expressions as described herein allmean introducing and transporting a stent through a bodily lumen into aregion that requires treatment by a mechanism such as a guidewire,balloon catheter, or other delivery system for self-expanding stents. Ingeneral, it is done by positioning a stent on one end of the guidewire,inserting the end of the guidewire through the bodily lumen of asubject, advancing the guidewire in the bodily lumen to a treatmentsite, and removing the guidewire from the lumen. The insertion may alsobe facilitated by other accessories such as a delivery sheath, a pushrod, a catheter, a pusher, a guide catheter, an endoscope, a cystoscope,or a fluoroscopy. Other methods of delivering a stent are well known inthe art.

The Manufacturing Process

Take metal stent frame for example:

1) Stent Manufacture

-   -   The stent frame can be laser cut from a metal tubing. After the        laser cutting, the stent frame will undergo an electro-polishing        process to make the edge of the stent frame smooth.        2) Base Layer Manufacture    -   Place the stent frame into a reservoir full of butylmethacrylate        (monomer). During the electro-grafting process, the        polymerization of butylmethacrylate will be initiated by some        initiators and the base layer (Poly-butylmethacrylate) will be        bonded (covalent bond) on the stent frame to provide surface        with a better biocompatibility.        3) Drug Containing Layer Manufacture        50/50 PLGA (biodegradable polymer) and Sirolimus (drug) is mixed        with a certain weight ratio and dissolved in chloroform to make        the spray solution. The stent frame with base layer is fixed        onto a rotator and spray coated with the spray solution.        Examples of Making the Stent Framework (2):

In some embodiments, the stent framework may comprise a pre-fabricatedmesh of magnesium alloy. The alloy may be fully biodegradable betweensix and nine months after implantation. Additionally or alternatively,the stent framework may maintain mechanical radical strength for atleast three months. Similarly, the stent framework may comprise apre-fabricated Poly-L-lactic acid (PLLA) or other biocompatible fullybiodegradable polymers. Such polymers may maintain the mechanicalradical strength for at least three months.

In some embodiments, the stent framework may be cut from a metal tubing,e.g., using a laser. An electro-polishing process may smooth the stentframework after cutting.

Examples of Making the Biocompatible Base Layer (5):

-   -   Electrochemical Reaction

In one embodiment, n-butyl methacrylate monomer may be dissolved intoN,N dimethyl formamide solvent (DMF). In certain aspects, sodiumchloride may be added as an electrolyte to increase the conductivity ofthe solution. The solution may be rotated and mixed for 120 minutes. Inone example, the concentration of methacrylate may be 20%, theconcentration of sodium chloride may be 5.0×10-2M, and the concentrationof DMR may be 80%.

A reactor containing the above primer layer coating solution may use anelectrochemical reaction to coat the stent framework with the solution.For example, the reactor may use a voltage of 20V to coat the frameworkat a pressure of 2 bar for approximately 120 minutes. The reactor mayinclude a nitrogen environment.

The biocompatible base layer may then be baked in vacuum (e.g., at 10mbar or less). In one example, the baking may occur at approximately 40°C. for 180 minutes. A biocompatible base layer formed with this processmay have a thickness of approximately 200 nm.

Examples of Making the Drug-Containing Layer (3):

In one embodiment, the drug-containing layer is applied to the stent viaa spray coating process. In other embodiments, the process ofapplication of the drug-containing layer to the stent (directly or onthe surface of the biocompatible base layer) comprises, for example,dipping, vapor deposition, and/or brushing.

Example 1 Spray Coating Process.

-   -   Process

In some embodiments, the drug-containing layer (3) may be formed using aspray coating process for disposing a polymer coating on the stentframework (or on a polymer-coated stent, e.g., a stent coated in theelectro-grated coating described below). In one example, a 20 millimeterlong electro-grafted stent was spray coated with biodegradable polyester(polylactide-co-glycolide 50/50, PLGA) containing Sirolimus. Thecopolymer (0.25% w/v) was dissolved in chloroform. Sirolimus was thendissolved in the chloroform/polymer mixture to obtain a final ratioSirolimus/polymer of (1/5). In another example, the mixture may comprise50/50 PLGA (e.g., 5 g) with rapamycin (e.g., 0.5 g) dissolved inchloroform (e.g., 600 mL). The mixture was then applied to the stent,mounted on rotative mandrel, by spraying with a fine nozzle with thefollowing parameters:

Spray parameter Spraying flow (μL/s) 24 Spraying volume (μL/s) 192Pressure (bar) 0.3 Stent rotation speed (rpm) 2000 Nozzle/stent distance(mm) 6.5 Number of spray run 50

Alternatively, such parameters may be adjusted by one of ordinary skillin the art to meet the conditions of this disclosure, to produce arun-even distribution of the drug layer on the stent surface (thinner onthe luminal face). In some embodiments, the parameters can be adjustedfrom those used in U.S. patent application Ser. No. 13/850,679(published as 2014/0296967 A1), U.S. patent application Ser. No.11/808,926 (published as 2007/0288088 A1), and U.S. Provisional PatentApplication No. 60/812,990, all of which are incorporated herein byreference in their entireties.

The conditions of the drug spraying may be adjusted so that thedrug-containing coating (3) may be applied to a luminal side (6),lateral side (7), and abluminal side (8) of the stent. See FIG. 10 . Dueto the high speed rotation spray and centrifugal effect, drug-containingcoating (3) may have a higher (and tunable) thickness on the abluminalside (facing the vessel wall) (8) with respect to the luminal side(facing the blood flow) (6) and the lateral side (7). An embodiment ofthis disclosure is a stent with such an un-even coating. In oneembodiment, relative high speed spinning, and low pressuring processover coating the stent with the drug-containing solution was found toproduce this result. Drying at 40° C. was then performed in a vacuumoven. Using the above parameters, the coating on this example stentweighs 800+/−80 μg and has a thickness of about 5-7 μm. The drug loadingin this example stent was 164+/−16 μg.

B. In Vivo Studies in Rabbits

Stents prepared by this method were used in vivo. A first stent wasprepared according to this example method with the following stentframework structure: In this example, the stent framework comprisedstainless steel with a 10 crest design. This design may result inimproved radial strength and greater uniformity after stent expansion ascompared with designs having fewer crests. The stent (cobalt chromium)possessed the following additional characteristics: conformal coatingwith a drug-containing layer of biodegradable polymer (PLGA, 3.5-10 um)with 1.4 ug/mm2 of Sirolimus; 80 um strut thickness; and anelectrografted durable/biocompatible base layer (supporting thedrug-containing layer) made of PBMA with a thickness of 100 nm-200 nm.

A number of stents with these properties were implanted into rabbits.All surgeries were performed using aseptic techniques. Rabbits wereplaced in a supine position and the hind-legs abducted and externallyrotated at the hips with the knees extended. During surgery to stabilizethe animal's physiologic homeostasis, animals were maintained on 0.9%Sodium Chloride, USP, intravenous drip at the rate of 10-20 ml/kg/hr andon warm water blanket. The animal's heart rate, blood pressure, bodytemperature, respiratory rate, O₂ saturation, CO₂ level, and theconcentration Isoflurane was monitored and recorded every 15 minutes.The left and right iliac arteries were injured by balloon endothelialdenudation. A 3.0 mm×8 mm standard angioplasty balloon catheter wasplaced in the distal iliofemoral artery over a guide wire usingfluoroscopic guidance and inflated to 8ATM with 50:50 contrast/saline.The catheter then was withdrawn proximally in its inflated stateapproximately to the level of the iliac bifurcation. The balloon wasdeflated, repositioned in the distal iliac, and vessel denudation at10ATM then was repeated over the same section of vessel initiallydenuded. Immediately following balloon denudation, coronary stents (BuMASupreme, Xience [Xience Xpedition], of BuMA BMS (3.0 mn×15.0 mm) wereimplanted in the denuded segment of the iliofemoral artery according tothe scheduled allocation. The pre-mounted stent/catheter was deliveredinto the distal iliofemoral artery over a guide wire using fluoroscopicguidance. Stents was deployed at the suggested nominal inflationpressures (10ATM) at a target balloon to artery ratio of 1.3 to 1.0delivered over 30 seconds. Repeat angiography was performed to assessstent placement and patency. Following post-implant angiography, allcatheters/sheaths were then withdrawn and surgical wound closed and theanimals recovered. For example, as shown in FIG. 3 , when a stentaccording to the present disclosure (Buma Supreme) was implanted in arabbit for 60 days, the stent exhibited a better endothelial coverage(80%) as compared with the Xience Xpedition depicted in FIG. 2 (50% asassessed by scanning electron microscopy (SEM).

Moreover, as shown in FIGS. 5A through 5D, after 60 days of implantationin a rabbit, a stent according to the present disclosure exhibited abetter functional endothelial coverage (38%) as compared with the XienceXpedition stent depicted in FIGS. 4A through 4D (21%).

As further shown in FIG. 7 , after 90 days of implantation in a rabbit,a stent according to the present disclosure exhibited a betterendothelial coverage (99%) as compared with the Xience Xpedition stentdepicted in FIG. 6 (70%).

Finally, as shown in FIGS. 9A through 9C, after 90 days of implantationin a rabbit, a stent according to the present disclosure exhibited abetter functional endothelial coverage (100%) as compared with theXience Xpedition stent depicted in FIGS. 8A through 8D (46%).

A second set of experiments was prepared according to this examplemethod with the following stent framework structure:

The stent (BuMA Supreme) was coated by the same spray coating processdescribed above with a conformal coating of biodegradable polymer(PLGA). The strut thickness was 80 um and the stent was made ofCobalt-Chromium alloy. The eG-layer was made of PBMA (100 nm-200 nm) andthe drug containing layer of PLGA (3.5 to 10 um) with 1.4 ug/mm2 ofsirolimus.

Similarly to the previous experiments, the stents were implanted intorabbits and their endothelialization was studied over time (e.g. 45 and90 days) using Evan's Blue and VE-Cadherin/P120 colocalization. Theresults are exemplified in FIGS. 12A through 12D for 45 days. Evan'sBlue; FIGS. 13A through 13D for VE-Cadhering/P120 colocalization at. 45days; FIGS. 14A through 14D for 90 days Evan's Blue; and FIGS. 5Athrough 15D for VE-Cadhering/P120 colocalization at 90 days. As shown inthese figures, stents according to the disclosure (BuMA Supreme stents)have a larger percentage of endothelial cell colocalization ofVE-Cadhering/P120 (i.e., the endothelium is better and more functional)than other drug eluting stents tested not according to the disclosure.In addition, the permissibility of the endothelial cell layer coveringthe stents of the disclosure (BuMA Supreme stents), as assessed byEvan's Blue staining, is lower than that of other tested drug elutingstents not according to the disclosure, indicating that the endotheliumis more functional in the BuMA Supreme stents.

It is also envisioned that the stent framework may comprise a wavedesign with an alternating pattern of two-three-two-three link polesspirally arranged in the axial direction. This design may improvebendability of the stent and may result in better fitting to the vesselafter stent expansion. In some embodiments, both ends of the stent mayhave two link poles or three link poles in accordance with thetwo-three-two-three pattern. In other embodiments, both ends of thestent may have four link poles, which may increase axial strength of thestent. Dimensions of this example design may include, for example, apole width of 90 μm, and a crown width of 100 μm. In having a crownwidth greater than the pole width, the stent may have grater radialstrength and have a reduced crossing profile with the vessel after stentexpansion. In addition, dimensions of this example design may include awall thickness of 80 μm or 90 μm.

-   -   C. Human Clinical Trials

Human clinical trials were performed with stents made of stainless steel(316L) (BUMA stents). The stents were designed to either have an OD: 1.6and 6 crests (first design) or an OD of 1.8 and 9 crests (seconddesign). The pole width of the first design was 110 μm and of the seconddesign 90 μm. The wall thickness of the first design was 100 μm and ofthe second design was 110 μm. These stents were coated by the spraycoating method described above.

A clinical trial titled “A prospective randomized controlled 3 and 12months OCT study to evaluate the endothelial healing between a novelsirolimus eluting stent BUMA and an everolimus eluting stent XIENCE V”was done. The BUMA stent was designed with a 30-day drug release timeframe and a 60-day coating/drug-containing layer bio-degradable timeframe and fabricated according to Example 1 above. On the other hand, aXience V stent is designed with a 120-day drug release time frame, andthe coating is bio-stable. Twenty patients were enrolled into the study.The BUMA and XIENCE V stents were overlapped implanted at the samelesion in the same vessel of the same patient. The study showed that thestruts of both stents were well-covered at 3 months and 12 months OCTfollow-tip. However, the struts of the BUMA stent had significantlycoverage compared to the struts of the XIENCE V stent at 12 months(99.2% BUMA vs. 98.2% XIENCE V with P<0.001). Moreover, the struts ofthe BUMA stent had a thicker neointimal hyperplasia thickness and largerneointimal area than the struts of the XIENCE V stent (0.15+0.10 mm BUMAvs. 0.12±0.56 mm XIENCE V with P<0.001). As explained above, a thicknessbelow a first threshold (e.g., 0.1 mm) may be indicative of aninsufficient number of endothelial cells while a thickness above asecond, higher threshold (e.g., 0.50 mm) may be indicative of a ratio ofsmooth cells to endothelial cells that is too high. In addition, theBUMA stent had a more uniform strut coverage compared to the XIENCE Vstent. The study shows that the BUMA stent had better long-term safetythan the XIENCE V stent.

Another clinical trial named “Biodegradable Polymer-BasedSirolimus-Eluting Stents With Differing Elution and Absorption Kinetics”was done. The BUMA stent was designed with a 30-day drug release timeframe and a 60-day coating bio-degradable(disappearance/dissolution/dissipation of the drug-containing layer)time flame and fabricated according to Example 1 above. The EXCEL stentwas designed with a 180-day drug release time frame and a 180-to-270-daycoating bio-degradable time frame. Two thousand three hundredforty-eight patients were enrolled into the study. The BUMA stentexhibited a lower incidence of stent thrombosis than the EXCEL stent. Inparticular, the 1-year rate of stent thrombosis was lower with the BUMAstent than the EXCEL stent, a difference that was evidenced within thefirst month after implantation.

Another clinical trial named “PIONEER-II Study” compared 1-month opticalcoherence tomography (OCT) results between a BUMA stent and a Xience Vstent. The BUMA stent was designed with a 30-day drug release time frameand a 60-day bio-degradable time frame for the drug containing layer andfabricated according to Example 1 above. The Xience V stent was designedwith a 120-day drug release time frame, and the coating was bio-stable.Fifteen patients were enrolled into the study. The study showed thatstruts neointimal coverage at 1-month by OCT follow-up for the BUMAstent exhibited better coverage compared to the Xience V stent (83.8%BUMA. vs. 73.0%, Xience V with P<0.001).

Example 2 Dispense Coating Process

-   -   A. Process

In some embodiments, the drug-containing layer (3) may be formed using adispense coating process to dispose a polymer coating on the stentframework (or on a polymer-coated stent, e.g., a stent coated in theelectro-grated coating described below). In one example, after drying, a20 millimeter stent was dispense coated with biodegradable polyester(polylactide, p-PLA) containing Sirolimus. The copolymer (5% w/v) wasdissolved in chloroform. Sirolimus was then dissolved in thechloroform/polymer mixture to obtain a final ratio 1:5 Sirolimus/polymerof 1/5). A micro dispenser was run along with the stent struts and linksand dispensed the mixture onto the abluminal side (8) of the stent by amicro dispenser using the following parameters:

Dispenser parameter Dispensing flow (μL/s) 10 Dispensing volume (μL/s)145 Pressure (bar) 0.1 Dispenser run speed (mm/s) 0.5 Dispenser/stentdistance (mm) 1.1 Number of dispenser run 10

The coating was applied to the abluminal side (8) of the stent only.Drying at 40° C. was performed in a vacuum oven. In this example, thecoating on the stent weighs 500±50 μg, and the coating thickness wasabout 9-12 μm. Moreover, in this example, the drug loading was 125±12μg.

-   -   The Electro-Grafted Coating (eG Coating)

In some embodiments, the biocompatible base layer (5) may furthercomprise/be made by an electro-grafted coating. More details about theprocess of electrografting coating of a stent are available in the art,including, for example, U.S. patent application Ser. No. 13/850,679(published as 2014/0296967 A1), U.S. patent application Ser. No.11/808,926 (Published as 2007/0288088 A1), and U.S. Provisional PatentApplication No. 60/812,990, all of which incorporated by referenceherein.

The electro-grafted layer may function as an adhesion primer for thedrug-containing layer (3) (e.g., during manufacturing crimping and/orstenting). The electro-grafted primer coating may be uniform. This layermay have a thickness between 10 nm and 1.0 micron, e.g., between 10 nmand 0.5 micron or between 100 nm and 300 nm. Such a thickness may ensurethat the coating does not crack. Electro-grafted layers are oftencapable of preventing the cracking, and delamination of biodegradablepolymer layers, and often exhibit equal, if not better recolonization,than stainless steel BMS. Furthermore, the use of an electro-graftedlayer having a thickness of at least about a few tens or of a hundrednanometers may secure a good reinforcement of adhesion of thedrug-containing layer (3) on account of interdigitation between the twopolymeric layers. Accordingly, the choice of the nature of theelectro-grafted polymer may be based upon the nature of the releasematrix polymer, which itself may be chosen on the basis of the loadingand kinetics of the desired drug release. In some embodiments, theelectro-grafted polymer and the release matrix polymers may be at leastpartially miscible in order to constitute a good interface. This is thecase when, for example, the two polymers have close solubility orHildebrand parameters, or when a solvent of one of the polymers is atleast a good swellant to the other.

In general, the electro-grafted polymer may be chosen from polymersknown to be biocompatible. For example, the polymers may be chosen fromthose obtained via propagation chain reaction, such as vinylics,epoxides, cyclic monomers undergoing ring opening polymerization, or thelike. Accordingly, poly-Butyl MethAcrylate (p-BuMA) poly-MethylMethAcrylate (PMMA), or poly-EpsilonCaproLactone (p-ECL) may be used.Alternatively or concurrently, Poly-HydroxyEthyl MethAcrylate (p-HEMA)may also be used.

The electro-grafted layer, (e.g., a p-BUMA layer) may further have apassivating behaviour and may block the release of heavy metal ions(e.g., in the blood flow or in the artery walls) from the stentframework. Said heavy metal ions may contribute to the initialinflammation caused by the introduction of the metal stent in the blood,which may provoke the partial oxidization of any metal until Nernstequilibrium is reached. In particular, the thickness of the artery wallsof the electro-grafted layer and biodegradable (with no drug) branch areusually smaller than those of the bare metal stent branch, evidencingless granuloma, i.e., less inflammation.

In one embodiment, the electro-grafted layer may be biodegradable, andthus may disappear from the surface of the stent after thedrug-containing layer has also disappeared.

The electro-grafted layer may have a non-thrombotic (orthromboresistant) effect and a pro-healing effect (e.g., promoting theproliferation and adhesion of active ECs). If the ECs startproliferating on the top of the drug-containing layer (e.g., before ithas fully disappeared), hydrolysis of the biodegradable polymers maynevertheless continue underneath, and the ECs may eventually contact theelectro-grafted layer. Such a pro-healing effect may be similar to thatof the stent framework if the electro-grafted layer is biodegradableitself. The pro-healing effect may be greater with a biostableelectro-grafted layer that secures proper recolonization by ECs in thelonger term.

In some embodiments, the electro-grafted layer may additionally be madeof anti-fouling materials.

The polymers which may be used as electro-grafted coating mentionincluding, but are not limited to, vinyl polymers, such as polymers ofacrylonitrile, of methacrylonitrile, of methyl methacrylate, of ethylmethacrylate, of propyl methacrylate, of butyl methacrylate, ofhydroxyethylmethacrylate, of hydroxylpropylmethacrylate, ofcyanoacrylates, of acrylic acid, of methacrylic acid, of styrene and ofits derivatives, of N-vinylpyrrolidone, of vinyl halides andpolyacrylamides, of isoprene, of ethylene, of propylene, of ethyleneoxide, of molecules containing a cleavable ring such as lactones and, inparticular, ε-caprolactone, of lactides, of glycolic acid, of ethyleneglycol, as well as polyamides, polyurethanes, poly(orthoesters),polyaspartates, or the like.

In some embodiments, the electro-grafted coating may be a vinylicpolymer or copolymer, such as poly butyl methacrylate (poly-BUMA), polyhydroxyethylmethacrylate (poly-HEMA), poly 2-methacryloyloxyethylphosphorylcholine/butyl methacrylate (poly-MPC/BUMA),poly-methacryloyloxyethyl phosphorylcholine/dodecylmethacrylate/trimethylsilylpropylmethacrylate (poly-MPC/DMA/TMSPMA), orthe like. In certain aspects, the electro-grafted coating may be abiodegradable polymer, such as a polycaprolactone, a polylactide (PL) ora polyglycolactide (PLGA).

-   -   Adhesion Between the Electro-Grafted Coating and the        Biodegradable Layer (Drug-Containing Layer or Topcoat Layer)

The drug-containing layer may adhere onto the electro-grafted layer byforming a chemical bond with the electro-grafted polymer; inserting, inthe electro-grafted polymer, chemical precursors of the drug-containinglayer, in order to provoke its formation inside the electro-graftedpolymer film; forcing the interpenetration of pre-formed biodegradablepolymer inside the electro-grafted layer by interdigitation, etc.Interdigitation generally relates to the fact that the polymeric chainsof the the biodegradable polymer may “creep” or “reptate” inside theelectro-grafted layer and may form at least one “loop” inside theelectro-grafted layer. For a polymer, one “loop” may refer to thetypical size of a chain when in a random configuration and may beevaluated using the radius of gyration of the polymer. Generally, theradius of gyration of a polymer is smaller than 100 nm, suggesting that,to enable improved adhesion, electro-grafted layers may be be thickerthan this threshold value to be capable of hosting at least one loop ofthe polymer(s) of the drug-containing layer.

In embodiments using interdigitation, the electro-grafted layer may bethicker than about 100 nm, may have a wettability (e.g.,hydrophobic/hydrophilic) identical to that of the polymer(s) of thedrug-containing layer, may have a glass transition temperature smallerthan that of the polymer(s) of the drug-containing layer, and/or may beat least partially swollen by a solvent of the polymer(s) of thedrug-containing layer or by a solvent containing a dispersion of thepolymer(s) of the drug-containing layer.

In some embodiments, interdigitation may be caused by spreading asolution containing the drug-containing layer (and optionally the drug)over a stent framework coated with an electro-grafted layer. Forexample, the drug-containing layer may comprise PLGA may be dissolved indichloroethane, dichloromethane, chloroform, or the like, optionallywith a hydrophobic drugs such as Sirolimus, Paclitaxel, ABT-578, or thelike. In such an example, the electro-grafted layer may comprise p-BuMA.

In some embodiments, this spreading may be performed by dipping or byspraying. In embodiments where spraying is used, a nozzle spraying theabove solution may face the stent framework, which may rotate in orderto present all outside surfaces to the spray. In certain aspects, thesolution to be sprayed may have a low viscosity (e.g., <1 cP, theviscosity of pure chloroform being about 0.58 cP), the nozzle may be atshort distance from the rotating stent, and the pressure of the inertvector gas (e.g., nitrogen, argon, compressed air, or the like) in thenozzle may be less than 1 bar. These conditions may lead to thenebulization of the liquid into small droplets of liquid, which maytravel in the spraying chamber atmosphere to hit the surface of theelectro-grafted layer of the stent. In embodiments where theelectro-grafted polymer layer and the spray solution have the samewettability, the droplet may exhibit a very low contact angle, and thecollection of droplets on the surface may therefore be filmogenic. Sucha spray system may enable the manufacturing of coated stents with verylittle webbing in between the struts.

The relative movement of the nozzle with respect to the stent may enablethe deposition of a uniform and/or relatively thin (e.g., <1 μm) layerin a single shot. The rotation and/or air renewal may enable theevaporation of the solvent, leaving the polymer layer (optionallyincluding the drug) on the surface. A second layer may then be sprayedon the first one and so on, in order to reach a desired thickness. Inembodiments where several sprays are used to reach the desiredthickness, the “low pressure” spray system may be implemented inbatches, in which several stents rotate in parallel with one nozzlespraying over each and every stent sequentially, therefore enabling theother stents to evaporate while another one is being sprayed.

In addition to these embodiments, the manufacturing process can compriseany of the methods of manufacturing disclosed in US20070288088 A1, whichis incorporated herein by reference.

The described embodiments are to be considered in all respects only asillustrative and not as restrictive. The scope of the present disclosureis, therefore, indicated by the appended claims rather than by theforegoing description. All changes which come within the meaning andrange of the equivalence of the claims are to be embraced within theirscope.

What is claimed is:
 1. A drug eluting stent, comprising: a stentframework; a drug-containing layer; a drug embedded in thedrug-containing layer; and a biocompatible base layer disposed over thestent framework and supporting the drug-containing layer, wherein thedrug-containing layer has an uneven coating thickness, wherein athickness of the drug-containing layer on a luminal side of the stentand a thickness of the drug-containing layer on a lateral side of thestent is less than a thickness of the drug-containing layer on anabluminal side of the stent; wherein said drug-containing layer and saidbiocompatible base layer are interpenetrated, forming an interdigitatedinterface without chemical bonding or layering.
 2. The drug elutingstent of claim 1, where the ratio between the thickness of thedrug-containing layer on the luminal side and the thickness of thedrug-containing layer on the abluminal side is between 2:3 and 1:7. 3.The drug eluting stent of claim 1, where the ratio between the thicknessof the drug-containing layer on the lateral side and the thickness ofthe drug-containing layer on the abluminal side is between 2:3 and 1:7.4. The drug eluting stent of claim 1, wherein the drug is embedded onlyon the drug-containing layer on an abluminal side of the stent.
 5. Thedrug eluting stent of claim 1, wherein the stent framework is fabricatedfrom a single piece of metal, wire, or tubing.
 6. The drug eluting stentof claim 5, wherein the metal comprises at least one of stainless steel,nitinol, tantalum, cobalt-chromium MP35N or MP20N alloys, platinum, andtitanium.
 7. The drug eluting stent of claim 1, wherein the stentframework is fabricated from a biodegradable material.
 8. The drugeluting stent of claim 1, wherein the drug comprises at least one of anantithrombogenic agent, an anticoagulant, an antiplatelet agent, anantineoplastic agent, an antiproliferative agent, an antibiotic, ananti-inflammatory agent, a gene therapy agent, a recombinant DNAproduct, a recombinant RNA product, a collagen, a collagen derivative, aprotein analog, a saccharide, a saccharide derivative, an inhibitor ofsmooth muscle cell proliferation, a promoter of endothelial cellmigration, proliferation, and/or survival, and combinations of the same.9. The drug eluting stent of claim 8, wherein the drug comprisessirolimus and/or a derivative or analog of sirolimus.
 10. The drugeluting stent of claim 1, wherein the drug-containing layer has athickness between 5 and 12 μm.
 11. The drug eluting stent of claim 1,wherein the drug-containing layer is selected from the group consistingof poly(hydroxyalkanoates) (PHAs), poly(ester amides) (PEAs),poly(hydroxyalkanoate-co-ester amides), polyacrylates,polymethacrylates, polycaprolactones, poly(ethylene glycol)(PEG),poly(propylene glycol)(PPG), poly(propylene oxide) (PPO), poly(propylenefumarate) (PPF), poly(D-lactide), poly(L-lactide), poly(D, L-lactide),poly(meso-lactide), poly(L-lactide-co-meso-lactide),poly(D-lactide-co-meso-lactide), poly(D,L-lactide-co-meso-lactide),poly(D,L-lactide-co-PEG), poly(D,L-lactide-co-trimethylene carbonate),poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylenecarbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG(PolyActive(R)), PEG-PPO-PEG(Pluronic(R)), and PPF-co-PEG,polycaprolactones, polyglycerol sebacate, polycarbonates, biopolyesters,polyethylene oxide, polybutylene terephalate, polydioxanones, hybrids,composites, collagen matrices with grouth modulators, proteoglycans,glycosaminoglycans, vacuum formed small intestinal submucosa, fibers,chitin, dexran and mixtures thereof.
 12. The drug eluting stent of claim11, wherein the drug-containing layer is selected from tyrosine derivedpolycarbonates.
 13. The drug eluting stent of claim 11, wherein thedrug-containing layer is selected from poly(β-hydroxyalcanoate)s andderivatives thereof.
 14. The drug eluting stent of claim 11, wherein thedrug-containing layer comprises a polylactide-co-glycolide 50/50 (PLGA).15. The drug eluting stent of claim 1, wherein the biocompatible baselayer comprises at least one of poly n-butyl methacrylate, PTFE,PVDF-HFP, poly(styrene-b-isobutylene-b-styrene), Parylene C, PVP, PEVA,SBS, PC, or TiO2.
 16. The drug eluting stent of claim 1, wherein thebiocompatible base layer comprises an electro-grafted polymeric layerhaving an interdigitated surface with the drug-containing layer.
 17. Thedrug eluting stent of claim 16, wherein the electro-grafted polymericlayer has a thickness between 10 nm and 1000 nm.
 18. The drug elutingstent of claim 16, wherein the electro-grafted polymeric layer comprisesa monomer selected from the group consisting of vinylics, epoxides, andcyclic monomers undergoing ring opening polymerization and aryldiazonium salts.
 19. The drug eluting stent of claim 18, wherein themonomer is further selected from the group consisting of butylmethacrylate, methyl methacrylate, hydroxyethyl methacrylate, epsiloncaprolactone, and 4-aminophenyl diazonium tetrafluoro borate.
 20. Thedrug eluting stent of claim 1, wherein the uneven thickness of thedrug-containing layer is achieved by spray coating of thedrug-containing layer.
 21. The drug eluting stent of claim 1, whereinthe thinner portion of the drug-containing layer releases the drugfaster than the thicker portion of the drug-containing layer, preferablywithin 10 to 20 days, wherein about complete release of the drug fromthe drug-containing layer occurs within 30 days of stent implantation.22. The drug eluting stent of claim 1, wherein the stent frameworkcomprises an 8 crest design.
 23. The drug eluting stent of claim 1,wherein the stent framework comprises a 10 crest design.
 24. The drugeluting stent of claim 1, wherein the stent framework comprises an 11crest design.
 25. The drug eluting stent of claim 1, wherein the stentframework comprises a plurality of stent poles having a wave design. 26.The drug eluting stent of claim 1, wherein the stent framework comprisesa plurality of single linking poles alternating between two linkingpoles and three linking poles between stent poles in an axial direction.27. The drug eluting stent of claim 1, wherein the stent frameworkcomprises four linking poles on a first end in an axial direction andcomprises four linking poles on a second end in the axial direction. 28.The drug eluting stent of claim 1, wherein a width of a crown is greaterthan a width of a pole.
 29. The drug eluting stent of claim 1, whereinthe stent is a non-stainless steel stent.
 30. The drug eluting stent ofclaim 1, wherein the stent comprises a cobalt-chromium alloy.